Paediatric deep brain stimulation
An Evidence Check rapid review brokered by the Sax Institute for the NSW
Ministry of Health. October 2019.
An Evidence Check rapid review brokered by the Sax Institute for NSW Ministry of Health.
October 2019.
This report was prepared by:
Ann Scott, Joanna Duncan, David Tivey, Wendy Babidge (ASERNIP-S of the Royal Australasian
College of Surgeons)
October 2019
This work is copyright. It may be reproduced in whole or in part for study training purposes subject
to the inclusions of an acknowledgement of the source. It may not be reproduced for commercial
usage or sale. Reproduction for purposes other than those indicated above requires written
permission from the copyright owners.
Enquiries regarding this report may be directed to the:
Principal Analyst
Knowledge Exchange Program
Sax Institute
www.saxinstitute.org.au
Phone: +61 2 91889500
Suggested Citation:
Scott A, Duncan J, Tivey D, Babidge W. Paediatric deep brain stimulation: an Evidence Check rapid review
brokered by the Sax Institute (http://www.saxinstitute.org.au/) for the NSW Ministry of Health, 2019.
Disclaimer:
This Evidence Check Review was produced using the Evidence Check methodology in response to
specific questions from the commissioning agency.
It is not necessarily a comprehensive review of all literature relating to the topic area. It was current
at the time of production (but not necessarily at the time of publication). It is reproduced for general
information and third parties rely upon it at their own risk.
Paediatric deep brain stimulation
An Evidence Check rapid review brokered by the Sax Institute for NSW Ministry of Health.
October 2019.
This report was prepared by Ann Scott, Joanna Duncan, David Tivey and Wendy Babidge.
ASERNIP-S of the Royal Australasian College of Surgeons
Contents
Glossary of terms ....................................................................................................................................................................................... 6
Abbreviations .............................................................................................................................................................................................. 8
Executive summary.................................................................................................................................................................................... 9
Background.............................................................................................................................................................................................. 9
Review questions ................................................................................................................................................................................... 9
Summary of methods .......................................................................................................................................................................... 9
Key findings ............................................................................................................................................................................................. 9
Gaps in the evidence ........................................................................................................................................................................ 10
Discussion of key findings .............................................................................................................................................................. 11
Conclusion ............................................................................................................................................................................................ 11
Background ............................................................................................................................................................................................... 12
Dystonia in childhood and adolescence ................................................................................................................................... 12
Current treatments ............................................................................................................................................................................ 13
Deep brain stimulation (DBS) ........................................................................................................................................................ 14
Methods ..................................................................................................................................................................................................... 15
Study selection .................................................................................................................................................................................... 15
Evidence grading and quality appraisal .................................................................................................................................... 16
Data extraction .................................................................................................................................................................................... 17
Included studies .................................................................................................................................................................................. 17
Findings....................................................................................................................................................................................................... 20
Quality appraisal results .................................................................................................................................................................. 20
Question 1: Safety, effectiveness and cost effectiveness of DBS compared with best supportive care ......... 20
Question 2a: Effectiveness of DBS for the various types of paediatric dystonia ...................................................... 20
Predictors of outcome...................................................................................................................................................................... 25
Question 2b: Safety of DBS for the various types of paediatric dystonia ................................................................... 26
Question 3: International service delivery models and funding mechanisms for paediatric DBS .................... 27
Gaps in the evidence ........................................................................................................................................................................ 28
Limitations ............................................................................................................................................................................................. 29
Discussion .................................................................................................................................................................................................. 30
Effectiveness ......................................................................................................................................................................................... 30
Safety....................................................................................................................................................................................................... 30
Cost and access considerations.................................................................................................................................................... 31
Knowledge gaps ................................................................................................................................................................................. 31
Considerations for future research ............................................................................................................................................. 31
Conclusion ................................................................................................................................................................................................. 33
Question 1: Safety, effectiveness and cost effectiveness of DBS compared with best supportive care ......... 33
Question 2a: Effectiveness of DBS for the various types of paediatric dystonia ...................................................... 33
Question 2a: Safety of DBS for the various types of paediatric dystonia ................................................................... 33
Question 3: International service delivery models and funding mechanisms for paediatric DBS .................... 33
The bottom line .................................................................................................................................................................................. 34
Appendix 1: Literature search strategy .......................................................................................................................................... 35
Appendix 2: Included studies ............................................................................................................................................................. 38
Appendix 3: Quality appraisal results ............................................................................................................................................. 50
Appendix 4: Efficacy data from primary studies ......................................................................................................................... 54
Appendix 5: Safety data from primary studies ........................................................................................................................... 57
References ................................................................................................................................................................................................. 60
6 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
Glossary of terms
Basal ganglia
The basal ganglia are deep-seated structures in the brain that are present in pairs, each having a right and a
left side counterpart. The individual brain structures that make up the basal ganglia are called the caudate
nucleus, putamen, globus pallidus, nucleus accumbens, subthalamic nucleus and substantia nigra.
Bilateral
Having or affecting two sides
Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS)
This is a universally applied instrument for the quantitative assessment of dystonia in both children and
adults.
Confidence interval (CI)
An estimated range of values that contains the true population value the study is intended to estimate;
usually reported as a 95% CI, i.e., the range of values you can be 95% certain contains the true value for the
population.
Deep brain stimulation (DBS)
A surgical procedure that uses electrical stimulation to deliver pulses to the brain; used to treat Parkinson’s
disease and other movement disorders such as dystonia and essential tremor
Dyskinesia
Abnormal movements that are disordered, impaired or excessive. The term may loosely imply various types
of extra or abnormal movements that are generally fast. The term is also commonly used to denote
abnormal movements that occur due to side effects of medications such as levodopa, a dopamine
augmenting drug.
Dystonia
A neurologic movement disorder characterised by sustained muscle contractions, causing repetitive,
patterned, involuntary, twisting or writhing movements and unusual posturing or positioning.
• Dystonia can be qualified as focal (affecting one part of the body, e.g. cervical dystonia), segmental
(affecting one segment of the body, e.g. the right shoulder, arm and hand) or generalised
• Primary dystonia: This is an older term to denote dystonia that occurs in the absence of brain injury or
visible abnormality on brain imaging
• Secondary dystonia: This is an older term to denote dystonia that occurs in the presence of brain injury
or with visible abnormality on brain imaging
Dystonia-parkinsonism
A combination of dystonia and parkinsonism in which either type of movement problem may be more
dominant than the other, or may follow the other with evolving disease course.
Globus pallidus
The globus pallidus is part of the basal ganglia deep within the brain. Specialised groups of nerve cells in
the globus pallidus act as a relay system to process and transmit information from the basal ganglia, via the
thalamus, to parts of the brain that regulate motor functions (e.g., the motor cortex). It is divided into two
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 7
parts: the globus pallidus externa and the globus pallidus interna (GPi). The GPi is a common target site for
placing deep brain stimulation electrodes for dystonia.
Intrathecal infusion
Administration of a drug into the space filled with cerebrospinal fluid that lies between the thin layers of
tissue covering the brain and spinal cord.
Levodopa
Levodopa is a drug used to treat Parkinson’s disease and other neurological movement disorders such as
dystonia and essential tremor.
Myoclonus
Sudden involuntary jerking of a muscle or group of muscles, which may be normal (e.g. a muscle jerk when
falling asleep) or a result of an underlying disease.
Parkinsonism
A group of neurological disorders characterised by decreased body movement (hypokinesia), tremor and
muscle rigidity
Prevalence
The total number of people with the disease at any one time.
Quality-adjusted life-year (QALY)
A measure of disease burden that takes into account the quantity and quality of life lived; it provides an
indication of the benefits gained from a given therapy in terms of quality of life and survival for the patient.
Subthalamic nucleus (STN)
An oval mass of grey matter that is one of the pairs of structures that make up the basal ganglia. The
subthalamic nuclei are located beneath a brain structure called the thalamus and are a common target site
for placing deep brain stimulation electrodes for parkinsonism.
8 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
Abbreviations
The following abbreviations are used throughout this report:
BFMDRS Burke-Fahn-Marsden Dystonia Rating Scale
BFMDRS-D Burke-Fahn-Marsden Dystonia Rating Scale disability
BFMDRS-M Burke-Fahn-Marsden Dystonia Rating Scale motor
CI Confidence interval
DBS Deep brain stimulation
FU Follow up
GA1 Glutaric aciduria type 1
GMFM-88 Gross Motor Function Measure-88
GPi Globus pallidus interna
HYS Hoehn and Yahr Scale
IQR Interquartile range
MPAN Mitochondrial kinase-associated neurodegeneration
PKAN Pantothenate kinase-associated neurodegeneration
QALY Quality-adjusted life-year
SD Standard deviation
SDy Status dystonicus
STN Subthalamic nucleus
SBRS Subjective Benefit Rating Scale
UMRS Unified Myoclonus Rating Scale
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 9
Executive summary
This Evidence Check rapid review was commissioned by the NSW Ministry of Health to review the evidence
on deep brain stimulation (DBS) for paediatric patients with severe dystonia.
Background
Dystonia is characterised by sustained or intermittent repetitive, involuntary muscle spasms that result in
unwanted abnormal movements, fixed postures or both. Paediatric dystonia may arise from a brain injury
(acquired), a genetic mutation (inherited) or an unknown cause (idiopathic). Childhood-onset dystonia
negatively affects growth, development and activity and can lead to progressive disability and deformity.
Instances of uncontrolled, prolonged dystonia, known as status dystonicus or dystonic storm, can result in
kidney damage, multiorgan failure and sometimes death.
There is no cure for dystonia, and its treatment in children is challenging because symptoms and treatment
response can vary depending on a child’s stage of development. Current best supportive care, which
comprises pharmacological treatments and physiotherapy, is limited by low efficacy and high rates of
adverse effects or both. As a result, DBS is increasingly being used to treat paediatric dystonia, sometimes as
a first-line treatment option, even though there are no formal guidelines on its use for this indication.
Review questions
The aim of this rapid review was to assess the peer-reviewed literature published within the last 10 years
with respect to the following questions:
1. Is paediatric DBS safe, efficacious and cost effective when compared with best supportive care?
2. Is DBS more safe or effective for some types of paediatric dystonia than others? Are there agreed
patient selection criteria?
3. What models of care and service delivery or access and funding mechanisms are established to deliver
paediatric DBS internationally?
Summary of methods
The peer-reviewed and grey literature was systematically searched to identify relevant studies and clinical
practice guidelines or consensus statements published between January 2009 and June 2019. The reference
lists of retrieved articles were also reviewed for potentially relevant studies. Abstract screening and study
selection were conducted by one reviewer according to predefined inclusion and exclusion criteria. The
methodological quality of the included studies was assessed using published quality assessment checklists,
and the evidence base was classified using the National Health and Medical Research Council (NHMRC)
dimensions of evidence. Data from the included studies were summarised narratively.
Sixteen papers met the inclusion criteria: one high quality systematic review, eight moderate- to high-
quality case series studies, six case reports and one clinical practice guideline. The overall NHMRC evidence
Grade was D (poor).
Key findings
Question 1
There were no studies identified that compared DBS with best supportive care in paediatric patients with
dystonia. It is unlikely that trials comparing these two interventions will be forthcoming in the short- or
10 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
long-term, given the small number of patients affected and the ethical issues of performing comparative
trials in this group.
Question 2
The evidence base comprised data on effectiveness outcomes for 457 patients and safety outcomes for 491
patients. With respect to the effectiveness of DBS for paediatric dystonia, generally consistent results from
Level IV evidence suggested the following:
• The best responders to DBS in terms of improved motor function are patients with idiopathic dystonia
or inherited dystonia without nervous system pathology
• Patients with inherited dystonia and nervous system pathology have comparatively lower, but still
clinically significant, improvement in motor function, particularly those with pantothenate kinase-
associated neurodegeneration or Lesch-Nyhan syndrome
• DBS is largely ineffective in improving motor function in patients with acquired dystonia, particularly
those with dyskinetic cerebral palsy
• DBS may be an effective treatment for halting life-threatening status dystonicus, although the number
of patients studied was small
• Other factors associated with a good response to DBS include older age at dystonia onset and truncal
involvement
• Age and severity of dystonia at surgery do not appear to affect treatment response
• It is unclear whether improvements in motor function translate to better quality of life and overall
health status.
With regard to the safety of DBS for treating paediatric dystonia, generally consistent results from Level IV
evidence suggested the following:
• The DBS implantation procedure is relatively safe, although patients who have the electrode and
impulse generator implanted in the same surgical session are more likely to experience a complication
in the first six months than those who have two-stage surgery
• The total risk of a complication requiring surgical intervention is 8% per electrode-year. The most
common complications that require additional surgery are hardware-related adverse events (range 17%
to 26%) and surgical site infections (range 7% to 13%), which generally occur at least six months after
the initial surgery
• Stimulation-induced side effects are rare, occurring in only 4% of patients
• The rates of adverse events do not differ among the dystonia subtypes
• Complications are most likely to occur in children aged 7–9 years and those with more severe dystonia.
Question 3
Aside from a single, outdated clinical practice guideline that made passing mention of the use of DBS in
paediatric patients with dystonia, no information was identified on service delivery models or funding
mechanisms for paediatric DBS.
Gaps in the evidence
There was limited evidence for Questions 1 and 3. For research Question 2, the evidence base was impacted
by the limitations inherent in retrospectively-collected data. Although the evidence for DBS in paediatric
inherited and idiopathic dystonia is promising, many questions remain. Data are sparse for patients with
acquired dystonia and its numerous aetiologies, and the effects of high-frequency neuromodulation on a
maturing brain are not yet known. It is also unclear how DBS affects pain, mood, quality of life and overall
health status, and whether there is an optimal implant site for each dystonia subtype. The economic impact
of a treatment begun in childhood that requires lifelong maintenance and follow-up also needs to be
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 11
assessed. Data from two recently established prospective multicentre registries are likely to help bridge
some of these knowledge gaps.
Discussion of key findings
Adequately assessing the effectiveness of DBS in children and adolescents is challenging. Many of the
commonly used measures of dystonia impairment, some of which are designed for use in adults, do not
capture more subjective factors such as wellbeing, quality of life and disease burden. Consequently, most
studies do not measure what matters most to children and their families. Future studies should include
severity scales and measures of quality of life, autonomy and pain in accordance with the World Health
Organization’s International Classification of Functioning, Disability and Health. It is also important that
studies have an adequate follow-up period, since the effects of DBS may be cumulative and could take at
least one year to stabilise in certain patient groups.
Conclusion
DBS has been used in children and adolescents with medically refractory idiopathic dystonia and inherited
dystonia without nervous system pathology for more than a decade. The growing body of Level IV evidence
generally supported this practice for improving motor function and disability, although more data need to
be collected on other aspects of patient wellbeing such as quality of life, cognitive function, pain and
autonomy. Patients with medically refractory inherited dystonia with nervous system pathology may also
benefit from DBS, but it is not yet clear which aetiologies within this subgroup would achieve the most
improvement from the treatment. DBS should also be considered for the emergency treatment of paediatric
patients experiencing medically refractory, life-threatening status dystonicus.
While DBS is generally well tolerated, it is associated with complications that may require repeat surgery,
and it requires ongoing, lifelong maintenance and follow-up from specialised providers.
12 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
Background
This Evidence Check rapid review was commissioned by the NSW Ministry of Health to review the evidence
on deep brain stimulation (DBS) for paediatric patients with severe dystonia. The rapid review focused on
the clinical effectiveness, safety and cost-effectiveness and patient tolerability of DBS, particularly with
respect to the different dystonia subtypes.
The NSW Ministry of Health will use this Evidence Check to guide further decision making in health service
prioritisation and planning for the treatment of paediatric dystonia in NSW.
Dystonia in childhood and adolescence
Dystonia is a relatively common neurological condition characterised by sustained or intermittent repetitive,
involuntary muscle spasms or stiffening that typically occur during attempted activity and result in
unwanted abnormal movements, fixed postures or both.1-3 It can manifest in a specific part of the body
(focal dystonia) or affect multiple muscle groups throughout the body (generalised dystonia), and may
occur in isolation (isolated dystonia) or in conjunction with other movement disorders (combined dystonia)
such as parkinsonism and myoclonus.4 Depending on the body area affected, the muscle spasms can be
painful and can severely impair an individual’s ability to eat, speak or walk.5, 6 Childhood-onset dystonia also
negatively affects growth, development, education and activity, and can lead to progressive disability and
deformity.3
Instances of uncontrolled, prolonged dystonia, known as status dystonicus or dystonic storm, are a medical
emergency. Status dystonicus may occur spontaneously or, in the case of certain dystonia typologies, be
triggered by an infection, medication or voluntary movement.7 The intense, unremitting muscle contractions
can cause breakdown of skeletal muscle and release of myoglobin into the bloodstream (rhabdomyolysis),
which can result in kidney damage, multiorgan failure and death (in up to 10% of patients).6-8
While the cause of dystonia is not fully understood, it is generally thought to result from abnormal
functioning of the basal ganglia in the brain.2, 9 The younger a person is at symptom onset, the more likely
the muscle spasms will spread to other parts of the body.4 Dystonia is classified according to three main
factors: the age at which symptoms develop; the areas of the body affected; and the underlying cause or
aetiology (acquired, inherited or idiopathic) (See Table 1).7
Acquired dystonia is the most common form of dystonia in the paediatric population.2, 10 In these cases,
damage to the brain’s motor network may arise from various causes including stroke, drug toxicity,
metabolic disturbances, poisoning, infection, autoimmune disorders, cortical maldevelopment, trauma,
neoplasms, neurodegenerative disease and perinatal hypoxia. Children with acquired dystonia often have
seizures or other neurodevelopmental disabilities.6, 11 Dyskinetic cerebral palsy, which is characterised by
uncontrolled, abrupt twisting movements, is the most common cause of acquired dystonia in children and
adolescents.11, 12 The prevalence of cerebral palsy is 1.7 to 3.1 per 1000 live births in high income countries,
and the dyskinetic form accounts for up to 15% of these cases.7, 13
Most inherited dystonias become apparent before the teenage years (mean age at onset is 12 years),
starting in one muscle group and progressively spreading to other parts of the body with increasing age,
often severely limiting function. Patients typically have normal intellect, but their ability to communicate
may be impaired.64, 7 A type of dystonia called DYT1 early-onset dystonia, caused by a mutation in the
TOR1A gene, is the most common inherited dystonia in children. It occurs in 1 in 160,000 children worldwide
and accounts for 16% to 53% of paediatric-onset dystonia in non-Jewish populations. The prevalence in
Ashkenazi Jewish populations is 1 in 3000–9000..4, 7, 14
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 13
Table 1: Current classification of dystonia1, 15
Dystonia Type Examples Previous Terminology
Inherited
Without nervous
system pathology
DYT1
DYT6
Myoclonus-dystonia
Segawa syndrome
Primary dystonia
Dystonia-plus
Inherited
With nervous
system pathology
Pantothenate kinase-associated
neurodegeneration
Glutaric aciduria type 1
Methylmalonic acidemia
Batten disease
Secondary dystonia
Heredodegenerative
dystonia
Acquired Cerebral palsy
Kernicterus
Stoke
Traumatic brain injury
Secondary dystonia
Idiopathic (unknown
cause)
Sporadic
Familial with no known genetic cause
Primary dystonia
Current treatments
There is no cure for dystonia, and treatment options are restricted by the limited understanding of its
aetiology and pathogenesis.3 Treating dystonia in children is challenging because their physiological,
cognitive and neuromuscular states vary with developmental stage, which can markedly affect disease
manifestation and treatment response.3, 7 Current treatments for paediatric dystonia aim to increase function
and quality of life by improving movement and posture, and are primarily based on extrapolation of data
from clinical trials in adults.3, 7
There are several pharmacological treatments for dystonia symptoms, including anticholinergic drugs,
dopamine augmenting or suppressing agents, baclofen and benzodiazepines (usually in combination with
other drugs such as baclofen).4, 6 The most common first-line treatment for segmental and generalised
dystonias is high-dose trihexyphenidyl (an anticholinergic drug), but its efficacy is poorly documented in
children and some studies have shown that children with dyskinetic cerebral palsy experience worsening of
symptoms.7, 14, 16 The side effects of anticholinergics include memory loss, confusion, restlessness,
depression, dry mouth and constipation.17
Botulinum toxin injections, which act locally and have fewer side effects than many systemic drugs, are used
to reduce disabling focal symptoms. However, repeat injections, for which children need sedation or
anaesthesia, are usually required every three to four months and the treatment is of limited use in
generalised dystonia.4, 7 Other drugs such as benzodiazepines, anticonvulsants and dopamine augmenting
or suppressing agents may provide benefit in select patient groups, but their use is generally limited.4 For
example, levodopa (a dopamine augmenting drug) is very effective in relieving symptoms of dopamine-
responsive dystonia (Segawa syndrome), a rare genetic disorder that causes defects in dopamine synthesis,
although the side effects include anorexia, nausea, vomiting, constipation, sedation, hallucinations, and
dyskinesia.14, 18
Continuous intrathecal infusion of baclofen (a muscle relaxant drug) via a mini pump implanted under the
abdominal fascia is used for generalised dystonia when oral medications have failed, particularly in children
who have dystonia and spasticity.14 Although baclofen has been shown to reduce spasticity in children with
cerebral palsy19, its effectiveness in reducing dystonic symptoms is less established.20, 21 The most common
14 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
side effects are sedation and nausea, but abrupt withdrawal, due to catheter malfunction or missed pump
refilling, can cause psychosis and life-threatening seizures.12, 17, 18Supportive therapies, such as physiotherapy
and occupational therapy, are often used in combination with pharmacological treatments, but the benefits,
if any, are often short-lived.17, 22
Overall, the current treatments for childhood dystonia are limited by low efficacy, high rates of adverse
effects or both.23 In addition, while these treatments may reduce the symptoms of dystonia, they do not
necessarily improve functional independence.
Deep brain stimulation (DBS)
The limited treatment options for children with dystonia have led to interest in the use of DBS for medically
refractory cases. DBS or neuromodulation uses high-frequency electrical impulses to block or modify the
irregular neuronal activity of the damaged brain region that causes dystonia.24
The DBS device is composed of a pulse generator and two electrode leads. With the patient under general
anaesthesia, tiny wire electrodes are inserted through small burr holes in the scalp into one or both sides of
the brain’s basal ganglia under magnetic resonance imaging (MRI) guidance. At the same time, or in a
separate procedure, a battery-powered pulse generator is implanted under the skin of the abdomen or
below the collarbone. The electrodes are connected to the pulse generator by insulated wires passed under
the skin down through the neck, and the amount of stimulation is adjusted according to symptoms.18, 24, 25
Since childhood dystonia is often generalised, the DBS electrodes are usually implanted bilaterally, most
commonly in the globus pallidus internus (GPi). However, the subthalamic nucleus (STN) and thalamus are
also sometimes targeted. The pulse generator batteries can be recharged by the patient at home using a
wearable recharging system, which means they may not need to be surgically replaced for up to 15 years.
Although there are no formal guidelines on indications for DBS in paediatric dystonia, there is a general
consensus that DBS therapy is useful as an option for primary generalised dystonia that is not readily
treated with medication. It is considered less useful in children with secondary dystonia because of the
extensive brain injury that is usually present.4, 18 Since optimal DBS stimulator settings for the various
dystonia types are not well established, frequent visits are often required to adjust settings, and benefits
from surgery may not be seen for weeks or even months.17 Although DBS is reversible, it is nonetheless a
life-long therapy that requires ongoing maintenance and follow-up.18 Its safety in children is unclear, and its
effects on the developing brain and musculoskeletal system and the natural course of disease are
unknown.3, 13
The aim of this rapid review was to assess the peer-reviewed literature published within the last 10 years on
the safety, clinical efficacy and cost-effectiveness of DBS for paediatric patients with dystonia. Information
was also sought on optimum methods for providing DBS services to patients with paediatric dystonia.
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 15
Methods
The aim of this rapid review was to address the following questions:
1. Is paediatric DBS safe, efficacious and cost effective when compared with best supportive care?
2. Is DBS more safe or effective for some types of paediatric dystonia than others? Are there agreed
patient selection criteria?
3. What models of care and service delivery or access and funding mechanisms are established to deliver
paediatric DBS internationally?
Study selection
A systematic literature search was conducted to identify relevant studies published between 1 January 2009
and 12 June 2019 (See Appendix 1). The search was developed and conducted prior to the study selection
process. The reference lists of retrieved articles were also reviewed for potentially relevant studies.
Titles and abstracts were screened by one reviewer and full-text publications of potentially relevant articles
were retrieved to determine their eligibility according to the predefined selection criteria listed in Table 2.
Primary and secondary research evidence
A best available evidence approach was used to select studies. Secondary research, such as systematic
reviews and health technology assessments, was preferentially included. Where there were two or more
systematic reviews with identical comparators and patient populations, only the most recently published
systematic review was included unless it was less comprehensive than the earlier review or an earlier review
presented a novel analysis of the evidence base. Eligible primary research published after the search end
date of the most recent systematic review was also included.
An article was deemed to be a systematic review if it met all of the following criteria: 26
• Focused clinical question
• Explicit search strategy
• Use of explicit, reproducible and uniformly applied criteria for article selection
• Critical appraisal of the included studies
• Qualitative or quantitative data synthesis.
If no suitable systematic reviews on the topic were available, eligible primary studies were selected for
inclusion. When overlapping patient groups were reported in studies, only the paper quoting the most
complete data set was used.
Studies were excluded if they: were included in a selected systematic review; were duplicate or preliminary
results; reported combined data from different populations and results for the population of interest could
not be disaggregated; were narrative reviews, editorials, study protocols or conference abstracts; or could
not be retrieved during the review period. Studies published prior to the literature search end date of the
most recent included systematic review were also excluded.
16 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
Table 2: Study inclusion criteria (PICO format)
Population Paediatric patients (≤20 years) encompassing the following age subcategories
as per Albanese et al.1:
• Infancy (birth to 2 years)
• Childhood (3–12 years)
• Adolescence (13–20 years)
Intervention Deep brain stimulation
Comparators Conventional best supportive care (medications and/or physiotherapy)
Outcomes Safety: Adverse effects, unintended consequences
Efficacy: Including, but not limited to movement severity, quality of life or
functional outcomes measured preoperatively and postoperatively with an
objective rating scale (e.g. Barry-Albright Dystonia Scale27, Burke-Fahn-Marsden
Dystonia Rating Scale28, Unified Myoclonus Rating Scale29, Canadian
Occupational Performance Measure30, Subjective Benefit Rating Scale31)a
Effects on family/carers
Direct or indirect costs
Study design Questions 1 & 2:
Systematic reviews with or without meta-analyses, health technology
assessments, interventional studies of any design, qualitative studies, cost-
effectiveness or other cost analyses and clinical practice guidelines
Question 3:
Clinical practice guidelines; other articles or studies of any design that contain
information on models of care and service delivery or access and funding
mechanisms for paediatric deep brain stimulation
Publication date 2009 onwards
Language English only
Note: PICO = Population, Intervention, Comparator and Outcome
aStudies evaluating DBS in patients with status dystonicus that did not use an objective rating scale were included
if they reported on resolution or recurrence of status dystonicus
Clinical practice guidelines
An article was deemed to be a clinical practice guideline if it met all of the following criteria:
• It contained the word “guideline” or “recommendation” in its title or introduction, or contained
recommendations on the use of DBS for paediatric dystonia
• It was developed by at least two authors
• It was evidence-based.
Although clinical practice guidelines that were not evidence based (e.g. consensus statements containing
recommendations based only on expert opinion) were originally excluded, this criterion was overridden
given the lack of such guidelines available.
Evidence grading and quality appraisal
The quality of a study refers to the extent to which it is has been designed and conducted to reduce bias in
the estimation of outcomes. One reviewer assessed the methodological quality of the included studies.
Systematic reviews were appraised with the AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews)
tool.32 AMSTAR is a 16-item checklist that assesses systematic reviews for quality of reporting and potential
biases in methodology and execution. Case series studies were assessed with a quality assessment checklist
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 17
developed by the Institute of Health Economics.33 This 20-item tool appraises the quality of the study’s
design, reporting, measurement of outcomes and data collection and analysis. The checklist was modified
by removing item 11, which pertains to whether outcome assessors were blinded to the intervention
received, because this is not applicable for patients receiving DBS. The quality of case reports and studies
included in a selected systematic review was not assessed. Quality assessment results were not used to
include or exclude studies.
The evidence presented in the selected studies was classified using the dimensions and levels of evidence
defined by the National Health and Medical Research Council (NHMRC).34, 35 These dimensions consider
important aspects of the evidence supporting a particular intervention and include three main domains:
strength of the evidence, size of the effect and relevance of the evidence.
Data extraction
Data were extracted by one reviewer using predetermined data extraction forms. Information extracted from
health technology assessments and systematic reviews included: the studies reviewed; funding sources and
conflicts of interest; inclusion and exclusion criteria; interventions; outcome measures; and relevant results
and conclusions. For primary studies, extracted information included: publication and study characteristics;
funding sources and conflicts of interest; study population and intervention details; type of outcomes
reported; and relevant qualitative and quantitative results. Information extracted from clinical practice
guidelines included guideline profile information (title, country, condition and intended users), the relevant
recommendations and noted evidence gaps. Study authors were not contacted for additional data.
Results were only extracted if they were stated in the text, tables, graphs or figures of the article, or could be
accurately extrapolated from the data presented. If no data were reported for a particular outcome, in
particular adverse effects, then no value was tabulated. This was done to avoid the bias caused by
incorrectly assigning a value of zero to an outcome measurement on the basis of an unverified assumption.
For example, a zero rate for intraoperative complications was only tabulated if it was specifically stated in
the study text that no intraoperative complications occurred in the patient sample.
Data from the included studies were summarised narratively. No statistical pooling of outcome data was
performed.
Included studies
A total of 951 potential studies were located during the literature database search, with an additional five
records identified by the grey literature search. After title and abstract screening, 75 full-text articles were
retrieved. On closer examination, 16 records met the eligibility criteria and were included as shown in
Figure 1. A summary table of the included studies is provided in Appendix 2.
In total, one systematic review15 was included plus eight case series studies36-43 and six case reports44-49
published after the systematic review, all of which represented level IV evidence. The systematic review by
Elkaim et al.15 summarised data on the effectiveness of DBS for 321 paediatric patients with dystonia from
72 unique primary studies (level IV evidence); the median follow up ranged from 11 to 20 months.
Four case series studies37-39, 42 and four case reports44, 47-49 published after Elkaim et al.15 documented safety
and effectiveness outcomes in a total of 151 patients (range 4–19 years) receiving DBS for various dystonia
aetiologies. Bilateral DBS of the GPi was undertaken in 92% of patients, with a postoperative follow up
ranging from six months to a mean of 4.6 years.
Five case series studies36, 37, 40, 41, 43 and two case reports45, 46 described safety and effectiveness outcomes for
16 patients (range 6–15 years) with various dystonic aetiologies who received DBS for status dystonicus. The
primary target for bilateral DBS was GPi in 89% of patients. Postoperative follow up ranged from six months
to 10 years.
18 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
Figure 1: Selection process for identifying relevant papers on DBS for paediatric dystonia
Effectiveness outcome data
The systematic review by Elkaim et al.15 focused exclusively on the effectiveness of DBS for paediatric
dystonia. It included 72 unique primary studies published from January 1999 to August 2017. In accordance
with current best practice for incorporating existing systematic reviews into new reviews,50 the results of
Elkaim et al.15 were summarised (the full texts of the primary studies were not retrieved). The evidence base
was then updated by including all relevant studies published from August 2017 to the current date.
Therefore, the evidence base for effectiveness in this Evidence Check covers the time period from January
1999 to June 2019 and comprises one systematic review, eight case series studies36-43 and five case
reports.45-49
Safety outcome data
Since safety was not the primary focus of the systematic review by Elkaim et al.15, complication rates were
not analysed in detail. Therefore, the full-texts of all studies (both included and excluded) cited in Elkaim et
al.15 that were published from 2009 onwards were retrieved. Where available, safety data were extracted
from studies that met the inclusion criteria for this rapid review (See Figure 2). This evidence was then
updated by including all relevant studies published from August 2017 to the current date. Therefore, the
evidence base for safety covers the time period from January 2009 to June 2019 and comprises 24 case
series studies and case reports sourced from Elkaim et al.15 plus seven case series studies36-39, 41-43 and four
case reports44-46, 48 published since August 2017.
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 19
Figure 2: Selection process for identifying relevant studies cited in Elkaim et al.15 that reported safety
outcomes
Other outcome data
There were no studies identified that analysed the cost effectiveness of DBS for paediatric dystonia.
A single guideline was identified that made recommendations on patient selection for DBS with some
reference to paediatric patients with dystonia.51
There were no articles identified that contained information on models of care and service delivery or access
and funding mechanisms for paediatric DBS.
20 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
Findings
In each section, evidence from secondary sources (systematic reviews) is presented first, followed by
findings from primary data sources.
Quality appraisal results
Quality appraisal results are provided in Appendix 3.
The included systematic review15 only represented level IV evidence because the evidence base comprised
solely case series and case reports. However, its overall quality of conduct and reporting was high, as rated
by AMSTAR 2, indicating that it is an accurate and comprehensive summary of the results of the available
studies. The review conducted a comprehensive literature search, provided sufficient descriptions of study
characteristics and inclusion criteria, pooled study results using an appropriate method, provided a list of
excluded studies, synthesised the data appropriately and had no notable conflicts of interest. The only non-
critical weakness was that it did not provide information on the conflicts of interest of the included primary
studies.
The quality of reporting was relatively high among the included case series studies (level IV evidence),
indicating a relatively low risk of bias (Figure 3). Six36-39, 41, 42 of the eight studies fulfilled at least 13 of the 19
quality criteria, with the other two40, 43 satisfying nine criteria. The studies all clearly described participant
characteristics and inclusion criteria as well as the reasons for losses to follow up, when they occurred. Most
of the studies measured outcomes and analysed the results appropriately. The main weaknesses were that
the majority of studies relied on retrospective data collection (only one study38 had definitely prospective
data collection), and 63% were from single centres and did not appear to have included consecutive
patients. In addition, not all of the studies were able to include patients at a similar point in their disease
status, and only half of the studies had an adequate follow-up length (≥ one year). However, many of these
issues are likely related to the rarity of the condition and the highly specialised nature of the treatment
being assessed, rather than a deficiency in study execution. None of the studies had any notable conflicts of
interest that were likely to bias the results.
Question 1: Safety, effectiveness and cost effectiveness of DBS compared with best supportive care
There were no comparative studies identified that compared paediatric DBS with best supportive care.
Question 2a: Effectiveness of DBS for the various types of paediatric dystonia
Effectiveness data from the systematic review are provided in Appendix 2, Table 2.1. Effectiveness data from
the primary studies are provided in Appendix 4.
Elkaim et al.15 included 72 unique case series or case reports (level IV evidence) on DBS in 321 children or
adolescents with dystonia of various aetiologies. In 12 of these patients, the diagnosis was either not stated
or was not recognised as having an aetiological link to dystonia. The combined Burke-Fahn-Marsden
Dystonia Rating Scale28 motor (BFMDRS-M) subscores for all dystonia types improved by a median 42%
(interquartile range [IQR] 12%-80%), with 86% of the 321 patients noting some improvement over their
preoperative state at the last follow-up (median 12 months). Clinically significant (≥20%) improvement was
recorded in 66% of patients. The median improvement in BFMDRS disability (BFMDRS-D) subscores was
28% in the 218 patients for whom this score was reported separately.
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 21
Figure 3: Quality appraisal results for included case series studies using the case series checklist33
The findings on the effectiveness of DBS to treat different types of paediatric dystonia are outlined below.
Inherited dystonia without nervous system pathology
Systematic review evidence (n=111 patients)
Elkaim et al.15 reported data for 111 patients who underwent DBS at a median age of 13 years (IQR 10–16).
Of these, 102 had confirmed DYT1 or DYT6 mutations and nine were diagnosed with myoclonus-dystonia
(seven of whom had DYT11 mutations). Bilateral GPi stimulation was performed in 107 patients. The
BFMDRS-M and BFMDRS-D subscores improved by a median 77% (IQR 53%–94%) and 70% (IQR 43%–86%),
respectively, with 93% of patients demonstrating some improvement and 88% having clinically significant
improvement (≥20%) in BFMDRS-M subscores at a median follow up of 13.5 months.
Patients with DYT1 or DYT6 dystonia had a median improvement of 78% (IQR 54%-94%) in BFMDRS-M
subscores and 70% (IQR 43%–86%) in BFMDRS-D subscores (median follow up 15 months), while those with
myoclonus-dystonia had improvements of 68% (IQR 36%–85%) and 50% (IQR 15%–85%; mean follow up
10.5 months), in the two subscores respectively. All of the latter nine patients with myoclonus-dystonia had
clinically significant improvement (≥20%): in five patients myoclonic movements improved by 83% on the
Unified Myoclonus Rating Scale29 (UMRS) action subscore and in one patient, the total score improved by
89%, compared with preoperative values.
Case series studies (n=21 patients)
Canaz et al.37 reported on four patients with primary dystonia who received bilateral implants in the GPi at a
median age of 12 years (range 5–16). Six months after surgery, the total BFMDRS scores had improved by a
median 43% (range 30%–45%) and the Subjective Benefit Rating Scale31i was 1.75 (standard deviation [SD]
i Worse (-1), no benefit (0), minimal benefit (1), good benefit (2), excellent benefit (3)
0 1 2 3 4 5 6 7 8
19. Competing interests & funding reported
18. Conclusions supported by results
17. Adverse events reported
16. Estimates of random variability reported
15. Losses to follow up reported
14. Length of follow-up adequate
13. Statistical tests appropriate
12. Outcomes measured before and after
11. Outcomes measured appropriately
10. Outcome measures established a priori
9. Co-interventions reported
8. Intervention clearly described
7. Similar point of entry in study
6. Inclusion/exclusion criteria stated
5. Participant characteristics described
4. Consecutive recruitment
3. Multicentre study
2. Study conducted prospectively
1. Hypothesis/aim/objective stated
Number of Case Series Studies
Cri
teri
on
Yes
Partially reported
No
Unclear
Not applicable
22 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
0.5). However, the Subjective Benefit Rating Scale is highly affected by patient expectations and does not
always correspond to the clinician’s evaluation.37
Candela et al.38 reported on six patients who underwent bilateral GPi DBS at a mean age of 12 years (range
7–16) for primary dystonia (n=4) or myoclonus-dystonia (n=2). Six months after surgery, the BFMDRS-M
and BFMDRS-D subscores had improved by a mean 58% (SD 33.4%) and 41% (SD 29%), respectively, in the
children with primary dystonia. For the two patients with myoclonus-dystonia, the improvements were 67%
and 93% for the BFMDRS-M subscore and 40% and 100% for the BFMDRS-D subscore. Six months after
surgery, improvements in myoclonic symptoms measured with the UMRS were 95% and 100% on the action
subscore, and 50% and 75% on the function subscore. Postoperative quality of life outcomes measured with
the Neuro-QOL scale52 were inconsistent. Six months after surgery, there were some improvements in upper
and lower limb function, stigma, social relationships and anger items, but scores for anxiety, fatigue, pain
and cognitive function were worse, compared with baseline values, and there was no change in depression
score.38
Tustin et al.42 assessed 11 patients who received bilateral GPi DBS at a mean age of 12 years (range 7–19).
Outcomes were measured using the Gross Motor Function Measure-8853 (GMFM-88) and the BFMDRS, but
the latter results were not extracted because they were previously reported by studies included in Elkaim et
al.15 The median improvement in gross motor function was statistically significant one year after surgery
(p=0.02), but this was not maintained in the six patients with two-year follow-up data.
Case reports (n=2)
Oterdoom et al.48 reported on the use of bilateral GPi DBS in a 9-year old patient with DYT6 mutation.
BFMDRS-M and BFMDRS-D subscores had improved by 46% and 3% over baseline values one year after
surgery. After 15 months, the patient’s condition deteriorated to status dystonicus, which required surgery
to reposition the electrodes. There was no further recurrence of status dystonicus up to 24 months after the
second surgery. By 3.4 years after the initial surgery, the BFMDRS-M and BFMDRS-D subscores had
improved by 42% and 10%, compared with baseline values.
Jones et al.47 used bilateral GPi DBS to treat a 15-year old patient with myoclonus-dystonia. Outcomes were
measured with the Canadian Occupational Performance Measure30, which captures a patient’s perceived
performance in everyday living. One year after treatment, the patient’s perceived performance score had
improved from 5.0 to 9.4 (parent rating 2.8 to 8.2) and the satisfaction score had improved from 2.6 to 9.6
(parent rating 2.2 to 8.8).
Inherited dystonia with nervous system pathology
Systematic review evidence (n=50)
Elkaim et al.15 reported data for 50 patients with inherited dystonia and nervous system pathology who
underwent DBS at a median age of 13.6 years (IQR 10 to 17). The BFMDRS-M subscores improved by a
median 27% (IQR 3%–60%), but there was there was no overall change in BFMDRS-D subscores at a median
follow up of 12 months. The subgroup of patients with pantothenate kinase-associated neurodegeneration
(PKAN) (n=36) or Lesch-Nyhan syndrome (n=4) demonstrated clinically significant improvement (≥20%) in
BFMDRS-M subscores (median 28% and 26%, respectively) at a mean 14.5 months after surgery, compared
with baseline values. Patients with glutaric aciduria type 1 (n=5) had the worst response, with a median
improvement in BFMDRS-M subscores of 6% at a median follow up of 12 months.
Case series and case reports (n=19)
Canaz et al.37 reported on two patients, aged 7 and 17 years at the time of surgery, who received bilateral
GPi DBS for dystonia related to PKAN and mitochondrial membrane protein-associated neurodegeneration.
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 23
Six months after surgery, the BFMDRS subscores had improved by 38% and 45%, and the Subjective Benefit
Rating Scale scores were 2 and 3, respectively.
Canaz et al.37 also reported on two patients, aged 14 and 16 years, with juvenile parkinsonism and focal
dystonia who received bilateral STN DBS. Six months after surgery, the Hoehn and Yahr Scale54 score had
improved from 2.5 (mild symptoms) and 3 (balance impairment, mild to moderate disease) preoperatively to
1 (symptoms on one side only) for both patients. After surgery both patients scored 3 on the Subjective
Benefit Rating Scale.
Tustin et al.42 reported on 14 patients with various inherited dystonia aetiologies that were associated with
nervous system pathology. After bilateral GPi DBS at a median age of 11 years (range 4 to 17), the median
GMFM-88 score was relatively unchanged one year after treatment and was worse than the preoperative
value by two years, although the latter change was not statistically significant.
Skogseid et al.49 reported on a 12-year old patient with an ACTB gene mutation who underwent bilateral GPi
DBS. Four years after surgery, the BFMDRS-M and BFMDRS-D subscores had improved by 66% and 44%,
compared with preoperative values.
Acquired dystonia
Systematic review evidence (n=76)
Elkaim et al.15 reported data for 76 patients (78% of whom had cerebral palsy) who underwent DBS at a
median age of 12 years (IQR 8 to 17). Among the 59 children and adolescents with cerebral palsy, the
BFMDRS-M and BFMDRS-D subscores improved by a median 11% (IQR 0%–21%) and 4% (IQR 0%–15%;
median follow up 12 months). Patients with kernicterus (n=8) and stroke (n=3) also showed little
improvement in BFMDRS-M subscores at a median follow-up of 12 months.
Case series and case reports (n=21)
Tustin et al.42 reported on 20 patients, 19 of whom had cerebral palsy. Bilateral GPi DBS performed at a
median age of 10.7 years (range 5.3 to 17.8) had minimal effect on GMFM-88 scores at either the one- or
two-year follow-up.
Canaz et al.37 reported on one patient with cerebral palsy who received bilateral GPi DBS at 8 years of age.
Six months after surgery, the child’s BFMDRS score had improved by 41% and the Subjective Benefit Rating
Scale score was 1.
Idiopathic dystonia
Systematic review evidence (n=72)
Elkaim et al.15 reported data for 72 patients who underwent DBS at a median age of 13.5 years (IQR 10 to
17). BFMDRS-M and BFMDRS-D scores improved by a median 51% (IQR 24%-73%) and 39% (IQR 20%-59%)
at a median follow up of 20 months. Clinically significant improvement (≥20%) in BFMDRS-M scores was
observed in 80% of patients.
Case series and case reports (n=15)
Tustin et al.42 reported results for 15 patients who received bilateral DBS at a median age of 12 years (range
7-19). Improvements in gross motor function were almost statistically significant at the one-year follow up,
but this was not maintained at the two-year follow up.
24 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
Status dystonicus
Systematic review evidence (n=18)
Elkaim et al.15 reported data for 18 patients receiving DBS for status dystonicus: six had DYT1 dystonia, five
had idiopathic dystonia, three had PKAN dystonia, two had Batten disease and two had idiopathic dystonia.
The dystonic crisis was resolved in 89% of the 18 patients. The BFMDRS-M subscores had improved a
median 54% (IQR 18%-89%) at last follow-up (median 11 months), and six patients had achieved over 85%
improvement, compared with preoperative values.
Case series and case reports (n=18)
Effectiveness data from the case series studies and case reports are provided in Table 3.
Koy et al.40 documented outcomes for five patients with GNAO1 mutation-induced status dystonicus
(duration not stated) who received GPi DBS at a mean age of 11.5 years (range 6–15; n=4 patients). The
crisis was resolved in all patients (time not stated), and four of the five patients had no relapses (longest
follow-up 10 years). One patient experienced multiple recurrences due to dysfunction of the DBS system.
Preoperative and postoperative BFMRDS-M and BFMRDS-D scores were reported for three patients; these
improved by a mean of 29% and 15%, respectively.
Benato et al.36 reported on four children (two with methylmalonic acidemia and two with GNA01 mutation)
who were treated with DBS for status dystonicus (mean duration 2.3 months) at a mean age of 9 years. The
STN was targeted in one patient and the GPi was targeted in the other three. Status dystonicus was resolved
in all cases within a mean 14 days, with no recurrence in four patients over the mean five-year follow-up
period. The modified Rankin Scale score55 improved from 5 (severe disability, requires constant care) to 4
(moderately severe disability, requires assistance for bodily needs) in all patients after surgery. One patient
experienced two more episodes of dystonic storm due to electrode displacement, which was resolved with
additional surgery.
Waak et al.43 reported on three children with GNAO1 mutation and cerebral palsy who received bilateral GPi
DBS for status dystonicus (duration not reported). Dystonic storm was resolved one to six weeks after
surgery, with no relapse occurring by the last follow up (range 12–26 months).
Canaz et al.37 reported on two patients, one with primary dystonia and the other with PKAN, who received
GPi DBS for status dystonicus (duration not reported) at the ages of 5 and 7 years. Dystonic storm was
resolved in both patients, with no relapses up to six months after surgery, and the BFMRDS score improved
by a mean 40%.
Lobato-Polo et al.41 reported on two patients aged 8 and 10 years of age with dyskinetic cerebral palsy who
underwent bilateral GPi DBS for status dystonicus (mean duration 5.5 days). Resolution of dystonic storm
was achieved 7 and 21 days after surgery, with no relapse occurring in the following 46 and 49 months
respectively. Improvement in the BFMRDS-M and Unified Dystonia Rating Scale54 scores ranged from 60%
to 61% and from 51% to 79%, respectively, at last follow up (range 46 to 49 months).
Barbosa et al.45 reported on a 13-year old patient with DYT1 mutation who underwent bilateral STN DBS for
refractory status dystonicus (three months’ duration). The crisis was resolved in 14 days and two months
after surgery, the BFMDRS-M score had improved by 57% compared with the preoperative value. There
were no relapses up to 10 months after surgery.
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 25
Table 3: Effectiveness data from primary studies on DBS for paediatric status dystonicus
N: total number of patients; PKAN: pantothenate kinase-associated neurodegeneration; SDy: status dystonicus aDue to dislocation of left electrode; no further recurrences after revision surgery bLoss of benefit due to dysfunction of DBS system requiring several lead replacements
Honey et al.46 treated a 10-year old patient with bilateral GPi DBS for GNAO1 mutation–induced status
dystonicus (two months’ duration). The crisis was resolved 10 days after surgery and no relapses occurred in
the six-month follow-up period. Scores on the Paediatric Barry-Albright Dystonia Scale and Caregiver
Priorities and Child Health Index of Life with Disabilities56 scale improved by 81% and 58%, respectively,
compared with preoperative values.
Predictors of outcome
Elkaim et al.15 conducted univariate (301 patients) and multivariable (77 patients from 38 studies)
hierarchical mixed-effects analyses to identify predictors of outcome. Patient factors associated with better
outcome included a diagnosis of idiopathic dystonia or inherited dystonia without nervous system
pathology; older age at dystonia onset; and truncal involvement (p<0.05). Age and severity of dystonia at
surgery were not associated with treatment response. Compared with the best responders, children and
adolescents with inherited dystonia with nervous system pathology had comparatively lower, but still
clinically significant, improvement, whereas patients with acquired dystonia did not generally benefit from
DBS.
Koy et al.39 grouped outcome data for 42 patients by dystonia aetiology as shown in Table 4. Since these
data could not be disaggregated, they are reported separately from the data in the preceding sections. The
majority of the patients received bilateral GPi DBS. The findings suggest that patients with acquired dystonia
benefited the least from treatment, which is in agreement with the findings in the Elkaim et al. analyses.
Study Diagnosis N Follow-up Rate of SDy
resolution (%)
Time to
resolution
Recurrence
rate (%)
Barbosa et
al. 45
DYT1 mutation 1 10 months 100% 2 weeks 0%
Benato et
al.36
Methylmalonic
acidemia (n=2)
GNAO1
mutation (n=2)
4 Mean 5
years
100% Mean 14 days 25%a
Canaz et
al.37
Primary
dystonia
PKAN
2 6 months 100% 2 weeks (n=1)
Not stated (n=1)
0%
Honey et
al. 46
GNAO1
mutation
1 6 months 100% 10 days 0%
Koy et al.40 GNAO1
mutation
5 Longest
follow-up
10 years
100% Not stated 20%b
Lobato-
Polo et al.41
Cerebral palsy 2 27 months 100% Range 7–21 days 0%
Waak et
al43
Cerebral palsy
and GNAO1
mutation
3 12–26
months
100% 1–6 weeks (n=2) 0%
26 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
Table 4: BFMDRS data from Koy et al.39 by dystonia type (mean follow up 4.6 years, range 1 month to 15
years)
Diagnosis N Preoperative
score
Postoperative
score p-value
Isolated inherited and idiopathic
dystonia
9 Mean 57.4
(SD 23.4)
Mean 27.6
(SD 16.3)
<0.05
Combined inherited and
idiopathic dystonia
22 Mean 67.7
(SD 33.6)
Mean 56.2
(SD 36.3)
<0.05
Acquired dystonia 11 Mean 71.0
(SD 28.3)
Mean 59.9
(SD 30.7)
Not statistically
significant
Combined groups 42 Mean 65.9
(SD 30.2)
Mean 52.1
(SD 33.8)
<0.05
BFMDRS: Burke-Fahn-Marsden Dystonia Rating Scale; N: total number of patients; SD: standard deviation.
Question 2b: Safety of DBS for the various types of paediatric dystonia
Thirty-five studies (level IV evidence) reported safety outcomes: 24 cited by Elkaim et al.15 (n=260 patients)
and 11 studies published after Elkaim et al.15 (n=159 patients). Data extracted from 34 of the studies are
tabulated in Appendix 5. An additional recently published study combined data from 10 DBS centres across
Germany and Vienna (n=72 patients).39
These data are reported separately at the end of this section.
For the majority of the 34 studies, it was not possible to disaggregate the data according to dystonia type in
any meaningful way. Safety outcomes were often reported anecdotally and without reference to the time
after surgery when they occurred, which hindered data pooling. Nonetheless, these data can be useful for
noting overall trends.
Among the studies that specifically mentioned complications in the early postoperative period (≤1 month
after surgery), hardware-related problems were the most commonly reported problem. Many studies did
not report the time after surgery when these malfunctions occurred, but in the few studies that did, these
complications usually happened at least six months after the surgery. Overall, electrode migration,
dislodgement or fracture occurred in 17% of 212 patients, all of whom required revision surgery to rectify
the problem. Recharger malfunction requiring replacement occurred in 30% of 168 patients, with pulse
generators unexpectedly switching off in 6% of 174 patients. Unspecified technical malfunctions occurred in
a further 7% of 184 patients.
Surgical site infections or seromas (a collection of fluid that builds up under the surface of the skin) were the
next most commonly reported adverse events, occurring in 9% (16/170) of patients within the first month of
surgery. Device removal was required in 30% of these 16 patients. These complications continued to be the
most commonly reported from one to six months after surgery, with surgical site infection or skin erosion
occurring in 14% (20/145) of patients; partial or complete device removal was required in 85% of these 20
patients. The overall rate of surgical site infection, irrespective of time after surgery, was 12% (48/412);
partial or complete device removal was required in 63% of the 48 patients. Stimulation-induced side effects,
such as hemiparesis, dyskinesia or slurred speech, were rare and generally mild or transient, occurring in 4%
of 215 patients. Only two of these patients found the side effects intolerable.
Koy et al.39 reported data from 72 patients categorised according to dystonia aetiology, with a mean
postoperative follow up of 4.6 years (1 month to 15 years). None of the patients experienced intraoperative
complications, and those occurring in the immediate postoperative period (≤1 month) were transient. The
most commonly reported complication during this period was cerebrospinal fluid collection around the
surgical site, which occurred in 10% of patients. Patients who received the electrode and impulse generator
implants in a single surgery (n=16) were more likely to experience adverse events during the first six months
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 27
than those who underwent two-stage surgery (n=14, p<0.05), although none of these complications were
infections. At least one surgical intervention was required in 13% (9/72) of patients for a wound infection
and in 26% (19/72) of patients for hardware problems. In line with the other studies, hardware-related
problems were the most common cause of complications at least one month after surgery. Most adverse
events occurred beyond the six-month follow-up period: 20% in the first six months and 56% thereafter
(n=55 patients with at least two years’ follow-up).
The total risk of a complication requiring surgical intervention was 8% per electrode-year (95% confidence
interval [CI] 5.9%–10.3%). The risk of experiencing a wound-related complication requiring surgical
intervention was 2% (95% CI 1.2%–3.6%), while the risk of an irreversible hardware-related event was 6% per
electrode-year (95% CI 4.1%–7.9%). The rates of adverse events did not differ according to dystonia
aetiology. However, there was a tendency for higher rates of complications beyond the six-month
postoperative period in patients aged seven to nine years of age, and in those with more severe dystonia at
surgery.
Question 3: International service delivery models and funding mechanisms for paediatric DBS
A single relevant evidence-based clinical practice guideline51 was identified, but it was published in 2011 and
its recommendations were based on literature published up to September 2009 (Table 5). Since the median
life span of a clinical practice guideline is five years from publication, this guideline is considerably
outdated.57, 58 However, it was the only guideline identified that specifically mentioned the use of DBS in
paediatric patients with dystonia, stating that age should not be a criterion for withholding GPi DBS. It did
not provide any information on service delivery models for paediatric DBS.
Table 5: Summary of recommendations from the included clinical practice guideline
Guideline
details • Recommendations
• Evidence gaps noted in
the guideline
Bronte-
Stewart et al.51
Multinational
Financial
support:
Not stated
Population:
Patients with
dystonia
Intended
Users:
Not stated
Age itself should not be used as an inclusion or exclusion
criterion for GPi DBS: children as well as adults can
benefit from the procedure. Any patient with a
progressive generalised dystonia should consider surgery
before developing fixed skeletal deformities.
GPi DBS should be considered for patients with
progressive generalised dystonia who do not respond
adequately to medical therapy and who are limited in
their activities of daily living.
For dystonic syndromes secondary to other causes, DBS
might be considered in cases of tardive dystonia,
hyperkinetic cerebral palsy, and/or cases with severe
disability, although more large prospective trials are
needed to support evidence of benefit.
Secondary dystonia from encephalitis and/or structural
lesions may not respond well to DBS.
Testing for DYT1 dystonia or myoclonus-dystonia (DYT11)
is helpful to confirm the diagnosis and for counselling
patients regarding outcomes of treatment.
More evidence is needed
on:
• The relative
contribution of age and
symptom duration on
surgical outcomes
• Which clinical features
are predictive of
response to DBS
• Outcomes related to
disability, quality of life
and non-motor
symptoms
• The efficacy of DBS in
other genetic dystonias
and secondary dystonia
syndromes
• Whether surgical
outcomes differ by
mutation status
28 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
Gaps in the evidence
There was a dearth of evidence for Questions 1 and 3. The absence of comparative studies meant that there
was no evidence available to answer research Question 1. Since DBS is currently considered a last resort
treatment reserved for children who have not responded to best supportive care, the latter may not be an
appropriate comparator for DBS. Unless the status of DBS in the care pathway changes, it is unlikely that
studies comparing DBS with best supportive care for paediatric dystonia will be forthcoming, particularly
given the small number of patients involved and the highly specialised nature of the treatment. Aside from a
single, outdated clinical practice guideline, there was a similar lack of information available to inform
research Question 3.
For research Question 2, the evidence base comprised small- to moderate-sized case series studies and
numerous, sometimes poorly-reported, case reports. The NHMRC evidence matrix for Question 2 is shown
in Table 6. While the quality of the recently published case series studies was relatively high, they
nonetheless suffered from the limitations inherent in retrospectively collected data. In addition, inclusion of
case reports and small case series studies, while necessary, may skew the results; patients who have good
outcomes are more likely to be reported than those who do not. The studies were often heterogeneous with
respect to study populations and the scales used to measure treatment effectiveness, which in the latter
case hampered synthesis of the data. However, the majority of the studies reported outcome data in a
manner that allowed disaggregation of results for the various dystonia aetiologies.
Table 6: NHMRC body of evidence matrix for research Question 2
aLevel of evidence determined from the NHMRC evidence hierarchy34, 35
Component A
Excellent
B
Good
C
Satisfactory
D
Poor
Evidence basea Several level I or II
studies with low risk
of bias
One or two level II
studies with low risk
of bias or a
SR/multiple level III
studies with low risk
of bias
Level III studies with
low risk of bias, or
level I or II studies
with moderate risk
of bias
Level IV studies, or
level I to III studies
with high risk of
bias
Consistency All studies
consistent
Most studies
consistent and
inconsistency may
be explained
Some inconsistency
reflecting genuine
uncertainty around
clinical question
Evidence is
inconsistent
Clinical impact Very large Substantial Moderate Slight or restricted
Generalisability Populations studied
in body of evidence
are the same as the
target population
Populations studied
in the body of
evidence are similar
to the target
population
Populations studied
in body of evidence
differ from target
population but it is
clinically sensible to
apply this evidence
to target
population
Populations studied
in body of evidence
differ from target
population and
hard to judge
whether it is
sensible to
generalise to target
population
Applicability Directly applicable
to Australian
healthcare context
Applicable to
Australian
healthcare context
with few caveats
Probably applicable
to Australian
healthcare context
with some caveats
Not applicable to
Australian
healthcare context
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 29
Limitations
This rapid review had some limitations. Only English-language studies were eligible for inclusion, and article
screening, study selection, data extraction and quality appraisal were conducted by a single reviewer. Study
authors were not contacted to obtain additional information. Also, the systematic review by Elkaim et al.15
comprised a substantial portion of the evidence base, which means that this Evidence Check shares that
review’s limitations. For example, Elkaim et al.15 included only studies that measured preoperative and
postoperative outcomes with either the BFMDRS or the Barry-Albright Dystonia Scale. Other outcome
measures, such as pain and function, were not included because they were often sporadically or
inadequately reported. While this was a valid rationale, it means that this Evidence Check, like the systematic
review, may have missed data on other outcomes such as pain and psychological wellbeing. However, after
reviewing full-text versions of a substantial number of the studies excluded by Elkaim et al.15, and given the
fact that the International Classification of Functioning, Disability and Health59 is rarely used to evaluate
DBS15, it is unlikely that any significant data were omitted. In addition, the criteria used by this Evidence
Check to select studies published after Elkaim et al.15 were expansive, which ensured that any data on
alternate outcomes were captured.
30 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
Discussion
This Evidence Check rapid review examined the evidence for using DBS to treat children and adolescents
with dystonia. The evidence base comprised data on effectiveness outcomes for 457 patients and safety
outcomes for 491 patients. Despite the limitations inherent in the mostly retrospective, level IV evidence
base, certain trends were evident.
Effectiveness
DBS targeted to the GPi provided significant improvement in BFMDRS scores for children and adolescents
with inherited dystonia without nervous system pathology, particularly those with DYT1-associated dystonia.
There was some suggestion that quality of life may also be improved, but the different measurement tools
used and sporadic reporting of these outcomes hindered more definitive conclusions. The small number of
patients with myoclonus-dystonia who received DBS also achieved significant improvements in both
dystonia and myoclonus symptoms. Children and adolescents with idiopathic dystonia benefited from GPi
DBS, with 80% of patients achieving significant improvements in BFMDRS scores. DBS was also an effective
treatment for life-threatening status dystonicus, although the number of patients studied was small. Other
factors associated with a good response to DBS included older age at dystonia onset and truncal
involvement, whereas neither age nor severity of dystonia at surgery was associated with a treatment
response.
In contrast, the outcomes for patients with inherited dystonia accompanied by nervous system pathology
were more variable and generally inferior, but still clinically significant. Within this dystonia subtype, the
BFMDRS scores were most improved in patients with PKAN or Lesch-Nyhan syndrome. The significant
improvement in motor score observed in a patient with an ACTB gene mutation suggests that other as yet
unidentified aetiological subgroups within this dystonia subtype may also derive benefit from DBS.
GPi DBS generally had minimal effect on BFMDRS scores in children and adolescents with acquired dystonia,
particularly in those with dyskinetic cerebral palsy. This was also the case for patients with dystonia due to
kernicterus or stroke, although the number of patients studied was very small.
Safety
While DBS is completely reversible, it is not without hazards. The procedure itself was relatively safe, but
surgical site infections and seromas occurred in 10% of patients within a month of surgery, with re-
intervention being required in nearly one-third of these cases. Hardware-related adverse events requiring
repeat surgery occurred in 17% to 26% of patients, usually at least six months after surgery. Recharger
malfunctions requiring replacement occurred in nearly a third of patients. However, stimulation-induced
side effects were rare, occurring in only 4% of patients. The total risk of a complication requiring surgical
intervention was 8% per electrode-year, and complication rates were similar across the various dystonia
subtypes. Children aged seven to nine years of age and those with more severe dystonia at surgery tended
to have a higher risk of complications than other patients.
Complication rates after DBS surgery are generally higher among children and adolescents than adults.12
Since DBS is a last resort treatment in paediatric patients, they have often spent a greater proportion of their
lives with severe dystonic symptoms.12, 18 The secondary complications associated with severe long-term
dystonia, such as sleep disturbances and feeding problems, can lead to low immunity and malnutrition,
which complicate postoperative recovery. In addition, children are more likely to experience hardware-
related problems, such as electrode dislocation and tight lead extensions, because of the changes in brain
volume, head circumference and body size that occur as they grow.12, 18, 37, 38
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 31
Cost and access considerations
While there was no information available on the cost-effectiveness of administering DBS to paediatric
patients with dystonia, Akano et al.60 noted that the average cost of hospitalisation in the United States (US)
for paediatric patients (mean age 14.5 years) undergoing DBS for various indications was approximately
$USD43,900 ($AUD63,500). Although this figure is not directly applicable to the Australian healthcare
context, it nonetheless highlights the significant resources required for this highly specialised treatment.
Additionally, close follow-up by an experienced team is essential for successful long-term maintenance of
DBS. This requires ongoing return visits, which may be difficult for patients who live far from experienced
providers.17
Most dystonic patients have lifelong care needs, which often start at a young age. An economic analysis by
Yianni et al.61, which used data from 26 patients undergoing DBS for dystonia (age not specified), estimated
that 63% of the total costs of DBS over a period of two years from the initial procedure were attributed to
preoperative and surgical costs, with only 37% contributed by follow-up management and complications.
While DBS is an expensive treatment, the upfront cost will likely be offset by the savings from reduced
medication use, fewer hospitalisations, decreased nursing care needs, improved quality of life, increased
participation in school and employment and decreased burden on family members and other caregivers.
Knowledge gaps
Although the evidence for DBS in paediatric primary dystonia is promising, many questions remain. Data are
sparse for patients with secondary dystonia and its numerous aetiologies. The effects of high-frequency
neuromodulation on a maturing brain are not yet known, although there is limited evidence from a small
study indicating that cognition may not be adversely affected.12, 62 One qualitative study63 has shown that
this may be an important consideration for parents of children who are less physically and cognitively
impaired because there is more to lose if the surgery does cause unintended harms. It is also unclear how
DBS affects pain, mood, quality of life and overall health status, and whether there is an optimal implant site
for each dystonia subtype.17, 18 The economic impact of a treatment begun in childhood that requires
lifelong maintenance and follow-up also needs to be assessed.64
Considerations for future research
Adequately assessing the effectiveness of DBS in children and adolescents is challenging. Although the
BFMDRS is the most commonly used measure of dystonia impairment, it is often criticised for not
discriminating between postures and movements caused by non-dystonic symptoms. Also, its accuracy for
measuring outcomes in children may not be ideal since it was originally designed for use in adults. Other
commonly reported scales such as the Barry-Albright Dystonia Scale and the UMRS either do not capture
more subjective factors such as wellbeing, quality of life and disease burden,3, 65 or may not be sensitive
enough to detect subtle improvements in pain and function that could be significant to patients.12, 66
Parents of children disabled by secondary dystonia make decisions about DBS surgery based on
expectations of potential improvements in physical and functional domains as well as quality of life (e.g.
pain relief)63, but these aspects are rarely reported even though moderate to severe pain is experienced by a
quarter of patients with secondary childhood dystonia.20, 66, 67 Future studies should include severity scales
and measures of quality of life, autonomy and pain in accordance with the International Classification of
Functioning, Disability and Health.3, 59, 68 It is also important that studies have an adequate follow-up period,
particularly since the effects of DBS may be cumulative and could take at least a year to stabilise in certain
patient groups.12, 69
Ongoing and recently completed clinical trials listed in the US National Library of Medicine database
ClinicalTrials.gov have compared DBS with sham, placebo or neuroablative treatment, or assessed technical
aspects such as different brain targets or devices, in patients with paediatric dystonia. In addition, the recent
32 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
establishment of two synchronised, prospective multicentre registries for paediatric DBS in Germany
(GEPESTIM) and the United States (the Pediatric International DBS Registry Project) should help answer
some of the outstanding questions relating to the use of DBS in paediatric patients with dystonia. As a case
in point, data on 72 patients from GEPESTIM were included in this Evidence Check.39
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 33
Conclusion
Question 1: Safety, effectiveness and cost effectiveness of DBS compared with best supportive care
No studies were identified that compared DBS with best supportive care in paediatric patients with dystonia.
Given the direction of current research efforts and the fact that DBS is considered a last resort in this patient
group, it is unlikely that trials comparing these two interventions will be forthcoming.
Question 2a: Effectiveness of DBS for the various types of paediatric dystonia
Generally consistent results from low-level evidence suggested the following:
• The paediatric patients who respond best to DBS in terms of improved motor function are those with
idiopathic dystonia or inherited dystonia without nervous system pathology
• Patients with inherited dystonia and nervous system pathology who undergo DBS have comparatively
lower, but still clinically significant, improvement in motor function, with most improvement seen in
patients with PKAN or Lesch-Nyhan syndrome
• DBS is largely ineffective in improving motor function in patients with acquired dystonia, particularly
those with dyskinetic cerebral palsy
• DBS may be an effective treatment for halting life-threatening status dystonicus, although the number
of patients studied was small
• Other factors associated with a good response to DBS include older age at dystonia onset and truncal
involvement
• Age and severity of dystonia at surgery do not appear to affect treatment response
• It is unclear whether improvements in motor function translate to better quality of life and overall
health status.
Question 2a: Safety of DBS for the various types of paediatric dystonia
Generally consistent results from low-level evidence suggested the following:
• The DBS implantation procedure is relatively safe, although patients who have the electrode and
impulse generator implanted in the same surgical session are more likely to experience a complication
in the first six months than those who have two-stage surgery
• The total risk of a complication requiring surgical intervention is 8% per electrode-year. The most
common complications that require additional surgery are hardware-related adverse events (range
17%–26%) and surgical site infections (range 7%–13%), which generally occur at least six months after
the initial surgery
• Stimulation-induced side effects are rare, occurring in only 4% of patients
• The rates of adverse events do not differ among the dystonia subtypes
• Complications are more likely to occur in children aged seven to nine years of age compared with other
age groups, and among those with more severe dystonia.
Question 3: International service delivery models and funding mechanisms for paediatric DBS
Aside from a single outdated clinical practice guideline that made passing mention of the use of DBS in
paediatric patients with dystonia, no information was identified on service delivery models or funding
mechanisms for paediatric DBS.
34 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
The bottom line
DBS has been used in children and adolescents with medically refractory idiopathic dystonia and inherited
dystonia without nervous system pathology for more than a decade, despite the lack of evidence-based
guidelines supporting its use in these patients. The growing body of level IV evidence considered in this
rapid review generally supported the use of DBS for improving motor function and disability, although more
data need to be collected on other aspects of patient wellbeing such as quality of life, cognitive function,
pain and autonomy. Patients with medically refractory inherited dystonia with nervous system pathology
may also benefit from DBS, but it is not yet clear which aetiologies within this subgroup would achieve the
most improvement. DBS should be considered as an option for the emergency treatment of paediatric
patients experiencing medially refractory, life-threatening status dystonicus.
While DBS is generally well tolerated, it is associated with complications that may require further surgery,
and it requires ongoing, lifelong maintenance and follow-up from specialised providers. Data from two
recently established prospective multicentre registries will help bridge the current knowledge gaps on the
use of DBS in children and adolescents with dystonia.
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 35
Appendix 1: Literature search
strategy
Databasea Search terms
PubMed 1 Exp “Child” (Subject Heading)
2 Exp “Child Health” (Subject Heading)
3 Child (All Fields)
4 Children (All Fields)
5 Child health (All Fields)
6 Exp “Pediatrics” (Subject Heading)
7 Pediatrics (All Fields)
8 Paediatrics (All Fields)
9 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8
10 Exp “Dystonia” (Subject Heading)
11 Exp “Torsion Dystonia” (Subject Heading)
12 Dystonia (All Fields)
13 Segawa syndrome (All Fields)
14 10 OR 11 OR 12 OR 13
15 Exp “Brain Depth Stimulation” (Subject
Heading)
16 Exp “Electrotherapy” (Subject Heading)
17 Deep brain stimulation (All Fields)
18 Deep brain stimulations (All Fields)
19 Brain stimulation, deep (All Fields)
20 Brain stimulations, deep (All Fields)
21 “Electrical stimulation of the brain” (All Fields)
22 Stimulation, deep brain (All Fields)
23 Stimulations, deep brain (All Fields)
24 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22
OR 23
25 Electrical (All Fields)
26 Electric (All Fields)
27 Electrode* (All Fields)
28 25 OR 26 OR 27
29 Stimulation (All Fields)
30 Brain (All Fields)
31 (28 AND 29) AND 30
32 24 OR 31
33 9 AND 14 AND 32
36 PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE
Databasea Search terms
Embase 1 Child (MeSH Term)
2 Child Health (MeSH Term)
3 Child (All Fields)
4 Children (All Fields)
5 Child health (All Fields)
6 Pediatrics (MeSH Term)
7 Pediatrics (All Fields)
8 Paediatrics (All Fields)
9 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8
10 Dystonia (MeSH Term)
11 Dystonia Musculorum Deformans (MeSH Term)
12 Dystonia (All Fields)
13 Segawa syndrome (All Fields)
14 10 OR 11 OR 12 OR 13
15 Deep brain stimulation (MeSH Term)
16 Electric Stimulation Therapy (MeSH Term)
17 Deep brain stimulation (all fields)
18 Deep brain stimulations (All Fields)
19 Brain stimulation, deep (All Fields)
20 Brain stimulations, deep (All Fields)
21 “Electrical stimulation of the brain” (All Fields)
22 Stimulation, deep brain (All Fields)
23 Stimulations, deep brain (All Fields)
24 OR 16 OR 17 OR 18 OR 19 OR 20 OR 21 OR 22
OR 23
25 Electrical (All Fields)
26 Electric (All Fields)
27 Electrode* (All Fields)
28 25 OR 26 OR 27
29 Stimulation (All Fields)
30 Brain (All Fields)
31 (28 AND 29) AND 30
32 24 OR 31
33 9 AND 14 AND 32
The Cochrane Library (Cochrane Database of
Systematic Reviews and the Database of Abstracts of
Reviews of Effects - Health Technology Assessment)
Dystonia; “deep brain stimulation”
Guideline agencies/repositories
Australian Clinical Practice Guidelines Portal Dystonia; “deep brain stimulation”
Canadian Medical Association Clinical Practice
Guideline Infobase
Dystonia; “deep brain stimulation”
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 37
Databasea Search terms
Guidelines International Network (G-I-N) Dystonia; “deep brain stimulation”
National Guidelines Clearinghouse (NGC) – until July
16, 2018
Dystonia; “deep brain stimulation”
National Institute for Health and Care Excellence
(NICE)
Dystonia; “deep brain stimulation”
Scottish Intercollegiate Guidelines Network (SIGN) Dystonia; “deep brain stimulation”
HTA and coverage agencies
Agency for Healthcare Research and Quality (AHRQ) Dystonia; “deep brain stimulation”
Aetna Clinical Policy Bulletins Dystonia; “deep brain stimulation”
BlueCross BlueShield Technology Assessments Dystonia; “deep brain stimulation”
Canadian Agency for Drugs and Technologies in
Health (CADTH)
Dystonia; “deep brain stimulation”
Institute for Clinical Evaluative Services (ICES) Dystonia; “deep brain stimulation”
Ontario Health Technology Advisory Committee
(OHTAC)
Dystonia; “deep brain stimulation”
National Institute for Health Research (NIHR) Health
Technology Assessment
Dystonia; “deep brain stimulation”
Relevant professional societies
American Association of Neurological Surgeons Dystonia; “deep brain stimulation”
European Academy of Neurology Dystonia; “deep brain stimulation”
Grey literature
Google Dystonia; “deep brain stimulation”
International Society for Pharmacoeconomics and
Outcomes Research (ISPOR)
Dystonia; “deep brain stimulation”
aLiterature search was conducted on 12 June 2019
Note: “*” is a truncation character that retrieves all possible suffix variations of the root word, e.g., Surg* retrieves
surgery, surgical, surgeon, etc.
Searches separated by semicolons were entered separately into the search interface
38 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Appendix 2: Included studies
Table 2.1: Included systematic review characteristics and data summary
Review Study Population Comparison/Outcome/
Intervention Details Relevant Results/Authors’ Conclusions
Elkaim et al.15
Canada
Objective:
To evaluate the efficacy of
DBS across dystonia
subtypes in children and
identify patient
phenotypes associated
with treatment response
Studies Reviewed:
72 case series and case
reports
Financial support:
No funding received; no
conflicts of interest
Methodological quality:
High (completely fulfilled
13/15 applicable criteria)
Included Patients:
Total number:
Status dystonicus: n=18
Dystonia: n=321
Inherited dystonia without
degeneration:n=111:
DYT1 or DYT6 mutations (n=102);
myoclonus-dystonia (n=9)
Inherited dystonia with
degeneration (n=50)
Acquired dystonia with static
lesions (n=76)
Idiopathic dystonia (n=72)
Other (diagnoses not generally
recognised as having an
etiological link to dystonia)
(n=12)
Condition:
Dystonia or status dystonicus
Age: ≤21 years of age
Exclusion Criteria:
Intervention:
DBS
Target:
Globus pallidus interna (GPi)
(n=309); STN only (n=3); STN
+ GPi (n=3); thalamus ± GPi
(n=3); pedunculopontine
nucleus + GPi (n=1); internal
capsule (n=1); not stated in
review (n=1)
Comparisons:
Not applicable; only case
series/reports available for
review
Outcomes:
Changes in the Burke-Fahn-
Marsden or Barry-Albright
rating scale, complications
Overall BFMDRS:
Motor subscore (n=312, median FU 12 months):
Median improvement: 42% (IQR 12%–80%); 86% showed
improvement
Clinically significant (≥20%) improvement: 66%
Disability subscore (n=218):
Median improvement: 28%
Inherited dystonia without degeneration (n=111, median FU
13.5 months) - BFMDRS:
Median improvement: 77% (IQR 53% to 94%) (motor subscore);
70% (IQR 43% to 86%) (disability subscore)
Clinically significant (≥20%) improvement: 88%
Subgroups:
DYT1/DYT6 dystonia (n=102): median improvement 78% (IQR 54%
to 94%) (motor); 70% (IQR 43% to 86%) (disability) (median FU 15
months)
Myoclonus-dystonia (n=9): median improvement 68% (median FU
10.5 months)
Inherited dystonia with degeneration (n=50, median FU 12
months) - BFMDRS:
39 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Studies published prior to
January 1999; studies without
individual patient data; studies
not reporting outcomes using the
Burke-Fahn-Marsden28Dystonia
Rating Scale (BFMDRS) or Barry-
Albright27 Dystonia Scale; data on
children with dystonia
parkinsonism
Median improvement: 27% (motor); 0% (disability)
Subgroups:
PKAN dystonia (n=36): median improvement 28% (motor)
Glutaric aciduria type 1 (n=5): median improvement: 6% (motor)
Lesch-Nyhan syndrome (n=4): mean improvement: 26% (motor)
(mean FU 14.5 months)
Acquired dystonia – BFMDRS (n=76, median FU 12 months):
Cerebral palsy (n=59): median improvement 11% (motor); 4%
(disability)
Kernicterus (n=8): median improvement 11% (motor); 4% (disability)
Stroke (n=3): mean improvement 11% (motor) (mean FU 12
months)
Idiopathic dystonia (n=72, median FU 20 months) - BFMDRS:
Median improvement: 51% (motor); 39% (disability)
Clinically significant (≥20%) improvement: 80%
Status dystonicus (n=18, median FU 11 months) - BFMDRS:
Median improvement: 54% (IQR 18% to 89%) (motor)
Crisis resolution (n=18): 89%
Responders to DBS:
• Best responders: idiopathic dystonia or patients with inherited
dystonia without degeneration (p<0.05)
• Worst responders: acquired dystonia
• Patients with inherited dystonia with nervous system pathology
had comparatively lower, but still clinically significant,
improvement
• Other factors associated with better outcome: older age at
dystonia onset and truncal involvement (p<0.05)
Safety:
40 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
DBS: deep brain stimulation; FU: follow up; IQR: interquartile range; GPi: Globus pallidus interna; STN: Subthalamic nucleus
The most commonly reported complications were infections and
mechanical failure.
Authors’ conclusion:
The data suggest that DBS is effective and should be considered in
selected children with inherited or idiopathic dystonia. Patients with
DYT1 dystonia tend to have better outcomes, but patients with
idiopathic dystonia also respond well.
Although less effective in other types of dystonia, DBS may be
considered because of the high number of medically refractory
patients. DBS should be considered as an emergency treatment for
status dystonicus.
41 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Table 2.2: Included primary study characteristics
Study Details Study Population Intervention
Outcomes Reporteda Conflicts of
interest Efficacy Safety
Quality
of Life
Case Series
Canaz et al.37
Turkey
Level IV evidence
(retrospective)
Methodological quality:
13/19 criteria fulfilled (1
not applicable)
Length of FU:
6 months
Losses to FU: 0%
Primary, secondary or heredodegenerative dystonia
or levodopa-responsive juvenile parkinsonism
refractory to medication (total n=9)
Subtypes:
Primary dystonia: n=4 (male)
Age at onset: mean 5.8 years (range 3–9 years)
Duration of symptoms: mean 5.5 years
Age at surgery: mean 11.3 years (range 5–16 years)
Juvenile parkinsonism: n=2 (female)
Age at onset: 11 and 14 years
Duration of symptoms: mean 2.5 years
Age at surgery: 14 and 16 years
Cerebral palsy: n=1 (female)
Age at onset: 0 years
Duration of symptoms: 8 years
Age at surgery: 8 years
MPAN dystonia: n=1 (female)
Age at onset: 9 years
Duration of symptoms: 8 years
Age at surgery: 17 years
PKAN dystonia: n=1 (female)
Age at onset: 5 years
Bilateral GPi DBS (n=7)
Bilateral STN DBS
(n=2 patients with
juvenile parkinsonism)
Pulse generator battery
type:
Not reported
Pulse generator location:
Chest or upper abdomen
depending on patient size
✓ ✓ None to
declare
42 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Study Details Study Population Intervention
Outcomes Reporteda Conflicts of
interest Efficacy Safety
Quality
of Life
Duration of symptoms: 2 years
Age at surgery: 7 years
Note: Two patients from this study also had status
dystonicus; data pertaining to that condition were
extracted separately
Candela et al.38
Spain
Level IV evidence
(prospective)
Methodological quality:
13/19 criteria fulfilled (1
not applicable)
Length of FU:
6 months
Losses to FU: 0%
Isolated or combined dystonia refractory to
medication (total n=6)
Age at onset: mean 5 years (range 2.5–10)
Duration of symptoms: mean 7 years (range 0.5–12)
Age at surgery: mean 11.8 years (range 7–16)
Subtypes:
Myoclonus dystonia: n=2 (female)
Primary dystonia: n=3 (2 female)
Choreo-dystonia: n=1 (male)
Bilateral GPi DBS
Pulse generator battery
type:
Rechargeable
Pulse generator location:
Abdomen
✓ ✓ ✓ 1 of 10 co-
authors has
received
honoraria
and financial
support for
research
from
Medtronic
Koy et al.39
Austria and Germany
Level IV evidence
(retrospective)
Methodological quality:
14/19 criteria fulfilled
Dystonia (total n=72; 46 male)
Age at onset (n=61): mean 4.4 years (SD 3.5)
Duration of symptoms: not stated
Age at first surgery: mean 12.3 years (SD 3.4; range 4-
18)
Bilateral GPi DBS (n=62)
Unilateral or bilateral STN
DBS (n=2)
Other targets (n=8)
✓ ✓ 4 of 27
authors
received
honoraria or
educational
support from
Medtronic
43 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Study Details Study Population Intervention
Outcomes Reporteda Conflicts of
interest Efficacy Safety
Quality
of Life
Length of FU:
mean 4.6 years (SD 4
years; range 1 month–15
years)
Losses to FU:
42% had missing
efficacy data
Subtypes:
Isolated inherited and idiopathic: n=16 (11 male)
Age at onset: mean 6.6 years (SD 2.3)b
Duration of symptoms: not stated
Age at surgery: mean 12.1 years (SD 3.3)
Combined inherited and idiopathic: n=34 (21 male)
Age at onset: mean 4.7 years (SD 3.4)b
Duration of symptoms: not stated
Age at surgery: mean 12.3 years (SD 3.3)
Acquired: n=22 (14 male)
Age at onset: mean 2.6 years (SD 3.5)b
Duration of symptoms: not stated
Age at surgery: mean 12.6 years (SD 3.7)
Pulse generator battery
type:
Rechargeable: 39%
Non-rechargeable: 49%
Unknown: 12%
Pulse generator location:
Below the clavicle or in
the abdomen
Tustin et al.42
United Kingdom (UK)
Level IV evidence (mixed
prospective/
retrospective)
Methodological quality:
13/19 criteria fulfilled
Length of FU: 2 years
Losses to FU:
Dystonic movement disorder (total n=60)
Subtypes:
Inherited dystonia without nervous system pathology:
n=11 (2 male)
Age at onset: median 7.7 years (range 0.5–10.4 years)
Proportion of life lived with dystonia: median 0.6 (range
0.11–0.97)
Age at surgery: median 11.8 years (range 7.3–18.8 years)
Inherited dystonia with nervous system pathology: n=14
(9 male)
Age at onset: median 2.0 years (range 0.5–9.8 years)
Bilateral GPi DBS
Pulse generator battery
type:
Not reported
Pulse generator location:
Not reported
✓ ✓ None to
declare
44 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Study Details Study Population Intervention
Outcomes Reporteda Conflicts of
interest Efficacy Safety
Quality
of Life
1-year: 3/60 (5%)
2-year: 7/48 (15%; only
48 patients had FU ≥2
years)
Proportion of life lived with dystonia: median 0.8 (range
0.07-0.95)
Age at surgery: median 11.1 years (range 4.2–17.4 years)
Acquired dystonia: n=20 (11 male)
Age at onset: median 0.2 years (range 0–14.3 years)
Proportion of life lived with dystonia: median 0.97
(range 0.14-1.0)
Age at surgery: median 10.7 years (range 5.3–17.8 years)
Idiopathic dystonia: n=15 (10 male)
Age at onset: median 2.5 years (range 0.3–13.0 years)
Proportion of life lived with dystonia: median 0.8 (range
0.25-0.98)
Age at surgery: median 12.2 years (range 6.8–18.6 years)
Benato et al.36
Italy
Level IV evidence
(unclear if prospective or
retrospective)
Methodological quality:
13/19 criteria fulfilled (2
not applicable)
Length of FU:
mean 5 years
Status dystonicus refractory to medication (total
n=4)
Age at onset: mean 5.5 years
Age at surgery: mean 9 years
Duration of status dystonicus: mean 2.3 months
Subtypes:
Methylmalonic acidemia: n=2 (female)
GNAO1 mutation: n=2 (female)
Bilateral GPi DBS (n=3)
Bilateral STN DBS (n=1
patient with
methylmalonic acidemia)
Pulse generator battery
type:
Not reported
Pulse generator location:
Not reported
✓ ✓ None to
declare
45 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Study Details Study Population Intervention
Outcomes Reporteda Conflicts of
interest Efficacy Safety
Quality
of Life
Losses to FU: 0%
Koy et al.40
France and Germany
Level IV evidence
(prospective)
Methodological quality:
9/19 criteria fulfilled (1
not applicable)
Longest FU:
10 years
Losses to FU: 0%
Status dystonicus refractory to medication (n=5; 3
male)
Age at onset: mean 4.4 years (range 0-11)
Duration of status dystonicus: not stated
Age at surgery (n=4): mean 11.5 years (range 6-15)
Subtype: GNA01 mutation
Bilateral GPi DBS
Pulse generator battery
type:
Not reported
Pulse generator location:
Not reported
✓ None to
declare
Lobato-Polo et al.41
Colombia
Level IV evidence
(retrospective analysis of
prospectively collected
data)
Methodological quality:
14/19 criteria fulfilled (2
not applicable
)
Status dystonicus refractory to medication (n=2;
male)
Age at onset: 0.1 and 1 year
Duration of status dystonicus: mean 5.5 days
Age at surgery: 8 and 10 years
Subtypes: dyskinetic cerebral palsy
Bilateral GPi DBS
Pulse generator battery
type:
Not reported
Pulse generator location:
nfraclavicular
✓ ✓ None to
declare
46 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Study Details Study Population Intervention
Outcomes Reporteda Conflicts of
interest Efficacy Safety
Quality
of Life
Length of FU:
27 months
Losses to FU: 0%
Waak et al43
Australia and UK
Level IV evidence
(retrospective)
Methodological quality:
9/19 criteria fulfilled (2
not applicable)
Length of FU:
mean 23.3 months
(range 16–28)
Losses to FU:0%
Status dystonicus refractory to medication (n=3; 1
male)
Age at onset: mean 6.3 months (range 3–12)
Duration of status dystonicus: Unclear
Age at surgery: mean 9.7 years (range 6–13)
Subtypes: dyskinetic cerebral palsy and GNAO1
mutation
Bilateral GPi DBS
Pulse generator battery
type:
Rechargeable (n=2)
Pulse generator location:
Not stated
✓ ✓ None to
declare
Case Reports
Jones et al.47
Australia
Level IV evidence
(retrospective)
Inherited dystonia without nervous system
pathology refractory to medication (n=1; female)
Subtype: Myoclonus dystonia
Age at onset: 4 years
Bilateral GPi DBS
Pulse generator battery
type:
Not reported
✓ ✓ None to
declare
47 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Study Details Study Population Intervention
Outcomes Reporteda Conflicts of
interest Efficacy Safety
Quality
of Life
Methodological quality:
Not applicable
Length of FU:
12 months
Losses to FU:
Not applicable
Duration of symptoms: 11 years
Age at surgery: 15 years
Pulse generator location:
Not reported
Oterdoom et al.48
Netherlands
Level IV evidence
(retrospective)
Methodological quality:
Not applicable
Length of FU:
2.4 years
Losses to FU:
Not applicable
Inherited dystonia without nervous system
pathology refractory to medication (n=1; male)
Subtype: DYT6 mutation
Age at onset: 3.5 years
Duration of symptoms: 5.5 years
Age at surgery: 9 years
Bilateral GPi DBS
Pulse generator battery
type:
Not reported
Pulse generator location:
Not reported
✓ ✓ None to
declare
Skogseid et al.49
Norway
Level IV evidence
(retrospective)
Methodological quality:
Inherited dystonia with nervous system pathology
refractory to medication (n=1; female)
Subtype: ACTB mutation
Age at onset: 12 years
Bilateral GPi DBS
Pulse generator battery
type:
Not reported
Pulse generator location:
✓ 2 of 9 co-
authors have
received
honoraria
from
Medtronic
48 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Study Details Study Population Intervention
Outcomes Reporteda Conflicts of
interest Efficacy Safety
Quality
of Life
Not applicable
Length of FU:
4 years
Losses to FU:
Not applicable
Duration of symptoms: 7 years
Age at surgery: 19 years
Not reported
Brimley and
Kershenovich44
US
Level IV evidence
(retrospective)
Methodological quality:
Not applicable
Length of FU:
22 months
Losses to FU:
Not applicable
Acquired dystonia (n=1; male)
Subtype: cerebral palsy
Age at onset: 7 years
Duration of symptoms: 2 years
Age at surgery: 9 years
Bilateral GPi DBS
Pulse generator battery
type:
Not reported
Pulse generator location:
Not reported
✓ None to
declare
Barbosa et al.45
Brazil
Level IV evidence
(retrospective)
Status dystonicus refractory to medication (n=1;
male)
Subtype: DYT1 mutation
Age at onset: 13 years
Bilateral STN DBS
Pulse generator battery
type:
Not reported
✓ ✓ None to
declare
49 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Study Details Study Population Intervention
Outcomes Reporteda Conflicts of
interest Efficacy Safety
Quality
of Life
Methodological quality:
Not applicable
Length of FU:
10 months
Losses to FU:
Not applicable
Duration of status dystonicus: 3 months
Age at surgery: 15 years
Pulse generator location:
Not reported
Honey et al. 46
Canada
Level IV evidence
(retrospective)
Methodological quality:
Not applicable
Length of FU:
6 months
Losses to FU:
Not applicable
Status dystonicus refractory to medication (n=1;
male)
Subtype: GNAO1 mutation
Age at onset: 1.5 years
Duration of status dystonicus: 2 months
Age at surgery: 10 years
Bilateral GPi DBS
Pulse generator battery
type:
Not reported
Pulse generator location:
Not reported
✓ ✓ ✓ None to
declare
DBS: deep brain stimulation; FU: follow up; GPi: globus pallidus internus; MPAN: mitochondrial membrane protein-associated; PKAN: pantothenate-kinase-associated
neurodegeneration; SD: standard deviation; STN: subthalamic nucleus aOnly outcomes measured with an objective rating scale were extracted bSome patients had missing data, but unclear how many
50 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Appendix 3: Quality appraisal
results
Table 3.1: Quality appraisal results for the included systematic review using the AMSTAR 2 checklist
Table 3.2: Quality appraisal results for included case series studies using the Institute of Health
Economics case series checklist
51 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Table 3.1: Quality appraisal results for the included systematic review using the AMSTAR 2 checklist32
Criterion Elkaim et al.15
1. Research questions and inclusion criteria included the PICOa components ●
2. Review methods were established a priori ◐
3. Selection of study designs for inclusion clearly explained ●
4. Comprehensive literature search strategy ●
5. Study selection performed in duplicate ●
6. Data extraction performed in duplicate ●
7. List of excluded studies provided with reasons for exclusion ●
8. Included studies adequately described ●
9. Satisfactory technique for assessing risk of bias in included studies NA
10. Sources of funding reported for included studies ◌
11. For meta-analysis, appropriate methods used to combine the results ●
12. For meta-analysis, the potential impact of risk of bias in individual studies on the results of the meta-analysis or
other evidence synthesis was assessed
●
13. Risk of bias was accounted for in individual studies when interpreting/discussing the results of the review ●
14. A satisfactory explanation was provided for any heterogeneity observed in the results of the review ●
15. For meta-analysis, an adequate investigation of publication bias was conducted ●
16. Potential sources of conflicts of interest were reported for the review authors ●
aPICO = population, intervention, comparator and outcome
Yes: ●; Partial yes: ◐; No: ◌; Unclear: ?; Not applicable: NA
52 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Table 3.2: Quality appraisal results for included case series studies using the Institute of Health Economics case series checklist33
Criterion Benato et
al.36
Canaz et
al.37
Candela et
al.38
Koy et al.40 Koy et al.39 Lobato-Palo
et al.41
Tustin et
al.42
Waak et
al.43
1. Hypothesis/aim/objective clearly stated ● ● ● ● ● ● ● ●
Stu
dy d
esi
gn
2. Study conducted prospectively ? ◌ ● ? ◌ ◐ ◐ ◌
3. Multicentre study ◌ ◌ ◌ ● ● ◌ ◌ ●
4. Participants recruited consecutively ? ● ? ? ? ● ● ?
Stu
dy p
op
ula
tio
n 5. Participant characteristics described ● ● ● ● ● ● ● ●
6. Participant eligibility clearly stated ● ● ● ● ● ● ● ●
7. Participants at similar entry point ● ◌ ◌ ● ◌ ● ◐ ●
Inte
rven
tin
s
8. Intervention(s) clearly described ● ● ● ◐ ◐ ● ◐ ◐
9. Co-intervention(s) clearly described ● ● ● ◌ ◌ ● ◌ ◌
Ou
tc o m e
m ea
sur
es 10. Outcome measures established a priori ● ● ● ◌ ● ● ● ◌
53 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Criterion Benato et
al.36
Canaz et
al.37
Candela et
al.38
Koy et al.40 Koy et al.39 Lobato-Palo
et al.41
Tustin et
al.42
Waak et
al.43
11. Outcomes measured appropriately ● ● ● ◐ ● ● ● ◌
12. Outcomes measured before and after the
intervention ● ● ● ◐ ● ● ● ◌
13. Appropriate statistical tests used NA NA NA NA ● NA ● NA
Resu
lts/
Co
ncl
usi
on
s
14. Length of follow-up adequate ● ◌ ◌ ◐ ● ● ● ?
15. Losses to follow-up reported ● ● ● ● ● ● ● ●
16. Estimates of random variability provided NA ● ● ◌ ● NA ● NA
17. Adverse events reported ● ● ● ● ● ● ◌ ●
18. Conclusions supported by results ● ● ● ● ● ● ● ●
19. Competing interests and funding reported ◐ ◐ ◐ ● ● ◐ ● ●
Reported: ●; Partially reported: ◐; Not reported: ◌; Unclear: ?; Not applicable: N/A
54 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Appendix 4: Efficacy data from primary studies
Study Diagnosis Outcome
measure N
Follow
up Preoperative Postoperative Absolute or % Change p-value
Inherited dystonia without nervous system pathology
Canaz et
al.37
NR BFMDRS 4 6 months
NR NR Median 43% (range 30%–
45%)
NR
SBRS NA Mean 1.75 (SD 0.5) -
Candela
et al.38
Primary
dystonia
BFMDRS-motor 4 6 months Mean 42.5 (SD 8.50) Mean 16.9 (SD 11.14) Mean 58% (SD 33.4%) NR
BFMDRS-
function
Mean 12.0 (SD 4.08) Mean 7.5 (SD 4.65) Mean 41% (SD 28.9%)
Total BFMRDS Mean 54.5 (SD 9.60) Mean 24.4 (SD 15.47) Mean 55% (SD 31.3%)
Myoclonus-
dystonia
BFMDRS-motor 2 6 months
Range 6–14 Range 1–2 Range 67%–93% NR
BFMDRS-
function
Range 2–5 Range 0–3 Range 40%–100%
Total BFMRDS Range 11–16 Range 1–5 Range 56%–94%
UMRS-
action
Range 19–28 Range 0–1 Range 95%–100%
UMRS-function Range 8–10 Range 2–5 Range 50%–75%
Total UMRS Range 50–72 Range 3–18 Range 75%–94%
55 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Study Diagnosis Outcome
measure N
Follow
up Preoperative Postoperative Absolute or % Change p-value
Tustin et
al.42
N=11
DYT1 (n=5)
GNAO1
(n=1)
Myoclonus-
dystonia
(n=1)
Other (n=4)
GMFM-88 11 1 year Median 78.4
(IQR 31.9–99.3)
Median 94.4
(IQR 81.4–99.4)
Median 6.4
(IQR 0.7–37.7)
0.02
6 2 years Median 98.6 (IQR 71.4–
99.7)
Median 14.5 (IQR -1.5–31.9) 0.1
Inherited dystonia with nervous system pathology
Canaz et
al.37
PKAN BFMDRS 1 6 months
NR NR 37.5% NR
SBRS NA 2 -
MPAN BFMDRS 1 6 months
NR NR 45% NR
SBRS NA 3 -
Juvenile
parkinsonis
m
HYS 2 6 months
Mean 2.75 Mean 1 NA NR
SBRS NA 3 -
Tustin et
al.42
N=14
PKAN (n=4)
GA1 (n=2)
Lesch-
Nyhan
(n=2)
Mitochondr
ial disorder
(n=3)
Other (n=3)
GMFM-88 13 1 year Median 29.1
(IQR 15.2–52.7)
Median 38.2
(IQR 26.3–57.7)
Median 0.8 (IQR -2.9–7.8) 0.4
12 2 years Median 28.8
(IQR 18.3–54.1)
Median -2.0
(IQR -15.6 to -0.7)
0.06
56 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Study Diagnosis Outcome
measure N
Follow
up Preoperative Postoperative Absolute or % Change p-value
Acquired dystonia
Canaz et
al.37
Cerebral
palsy
BFMDRS 1 6 months NR NR 41% NR
SBRS NA 1 -
Tustin et
al.42
N=20
Cerebral
palsy
(n=19)
Brain injury
(n=1)
GMFM-88 19 1 year Median 31.3 (IQR 15.9–
48.9)
Median 34.6
(IQR 18.8–59.1)
Median 0.9 (IQR -2.5–5.6) 0.2
13 2 years Median 41.5
(IQR 15.3–50.4)
Median 0.1 (IQR -4.2–3.6) 0.9
Idiopathic dystonia
Tustin et
al.42
N=15
GMFM-88 14 1 year Median 85.8
(IQR 16.8–92.7)
Median 81.3
(IQR 36.1–94.0)
Median 2.2 (IQR -0.9–9.7) 0.06
10 2 years Median 71.3
(IQR 39.7–91.0)
Median 5.2 (IQR -3.1–19.2) 0.2
BFMDRS: Burke-Fahn-Marsden Dystonia Rating Scale; FU: follow up; GA1: Glutaric aciduria type 1; GMFM-88: Gross Motor Function Measure; HYS: Hoehn and Yarh Scale; IQR:
interquartile range; MPAN: mitochondrial membrane protein-associated neurodegeneration; N: total number of patients; NA: not applicable; NR: not reported; PKAN:
pantothenate kinase-associated neurodegeneration; SBRS: Subjective Benefit Rating Scale; SD: standard deviation; UMRS: Unified Myoclonus Rating Scale
57 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Appendix 5: Safety data from primary studies
Adverse effect Proportion of patients (n/N)
Intraoperative outcomes
No intraoperative complications 1/146
Postoperative outcomes Not stated ≤1 month ≤3 months ≤6 months >6 months
No postoperative complications 39/3931, 70-77
Surgical site infection 1/343
Resolved without device removal 1/241
1/578
2/12679
Requiring complete/partial device removal 1/1380
3/13142
2/1281
3/3182
1/383
1/184 13/12679a
2/585
1/937
1/186
2/3182b
Total 3%
(6/156)
Total 12%
(4/34)
Total 11%
(16/140)
Total 9%
(3/32)
Seroma at surgical site resolved without device removal 10/12979
Skin erosion
Resolved without device removal 1/436
Requiring complete/partial device removal 3/12979
Cerebrospinal fluid collection in pulse generator pocket
or scalp burr hole
2/3182 1/12979
Asymptomatic intracranial haemorrhage 1/1187
1/12979
58 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Adverse effect Proportion of patients (n/N)
Total 1%
(2/140)
Pneumonia 1/578
Hemiparesis 1/3182
Intolerable stimulation-induced side effects 2/12979
Slurred speech 1/688 2/638
1/145
Mild decline in verbal fluency 1/389
Transient dyskinesia 1/688
Hardware-related problems
Technical defect/malfunction (unspecified) 8/13142
5/1480
Total 9%
(13/145)
Inaccurate electrode placement requiring revision 2/3182 1/290 1/148
1/138
Lead/electrode migration/ dislodgement requiring
complete/partial device removal
1/1187
3/12979
1/343
1/436 1/191
1/1380
1/144
Total 4%
(5/143)
Total 20%
(3/15)
59 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
Adverse effect Proportion of patients (n/N)
Electrode/lead defect/fracture requiring revision 1/1187
2/1480
16/12979
2/3182
1/383
1/290
1/578
1/148
Total 12%
(22/188)
Total 38%
(3/8)
Loss of effect requiring revision/removal 2/290
Impulse generator migration
Short/tight extension lead due to growth 5/12979
Pain associated with lead/impulse generator location 1/192
Recharger malfunction requiring replacement 49/12979
Impulse generator switched off unexpectedly 9/12979 1/638
a8% for children younger than 7 years (2/26)
bHardware infection occurred in 57% (4/7) of children younger than 10 years, whereas the infection rate for children older than 10 years was 0% (p=0.001), regardless of diagnosis.
Note: Nearly all of the surgeries were first-time DBS operations
60 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
References
1. Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, et al. Phenomenology and Classification of
Dystonia: A Consensus Update. Mov Disord. 2013;28(7):863-73.
2. Lumsden DE, Gimeno H, Lin JP. Classification of Dystonia in Childhood. Parkinsonism Relat Disord.
2016;33:138-41.
3. Elkaim LM, De Vloo P, Kalia SK, Lozano AM, Ibrahim GM. Deep Brain Stimulation for Childhood Dystonia:
Current Evidence and Emerging Practice. Expert Review of Neurotherapeutics. 2018;18(10):773-84.
4. Zorzi G, Carecchio M, Zibordi F, Garavaglia B, Nardocci N. Diagnosis and Treatment of Pediatric Onset
Isolated Dystonia. European Journal of Paediatric Neurology. 2018;22(2):238-44.
5. F C. Movement and Postural Control in Dystonia Patients. Brain Foundation; 2014. [Access Date: July 24].
Available from: https://brainfoundation.org.au/research-grants/2014/dystonia-2/
6. Kruer MC. Pediatric Movement Disorders. Pediatrics in Review. 2015;36(3):104-16.
7. Koy A, Lin JP, Sanger TD, Marks WA, Mink JW, et al. Advances in Management of Movement Disorders in
Children. The Lancet Neurology. 2016;15(7):719-35.
8. Lumsden DE, Allen NM. Rethinking Status Dystonicus: A Welcome Start to a Challenging Problem. Mov
Disord. 2018;33(2):344.
9. Surgeons AAoN. Dystonia. American Association of Neurological Surgeons; 2019. [Access Date: July 24].
Available from: https://www.aans.org/Patients/Neurosurgical-Conditions-and-Treatments/Dystonia
10. McClelland VM. The Neurophysiology of Paediatric Movement Disorders. Current Opinion in Pediatrics.
2017;29(6):683-90.
11. Lin JP, Lumsden DE, Gimeno H, Kaminska M. The Impact and Prognosis for Dystonia in Childhood Including
Dystonic Cerebral Palsy: A Clinical and Demographic Tertiary Cohort Study. J Neurol Neurosurg Psychiatry.
2014;85(11):1239-44.
12. Koy A, Timmermann L. Deep Brain Stimulation in Cerebral Palsy: Challenges and Opportunities. Eur J
Paediatr Neurol. 2017;21(1):118-21.
13. Monbaliu E, Himmelmann K, Lin JP, Ortibus E, Bonouvrie L, et al. Clinical Presentation and Management of
Dyskinetic Cerebral Palsy. Lancet Neurol. 2017;16(9):741-49.
14. Fernandez-Alvarez E, Nardocci N. Update on Pediatric Dystonias: Etiology, Epidemiology, and
Management. Degener Neurol Neuromuscul Dis. 2012;2:29-41.
15. Elkaim LM, Alotaibi NM, Sigal A, Alotaibi HM, Lipsman N, et al. Deep Brain Stimulation for Pediatric
Dystonia: A Meta-Analysis with Individual Participant Data. Developmental Medicine and Child Neurology.
2019;61(1):49-56.
16. Sanger TD, Bastian A, Brunstrom J, Damiano D, Delgado M, et al. Prospective Open-Label Clinical Trial of
Trihexyphenidyl in Children with Secondary Dystonia Due to Cerebral Palsy. J Child Neurol. 2007;22(5):530-
7.
17. Jinnah HA, Factor SA. Diagnosis and Treatment of Dystonia. Neurol Clin. 2015;33(1):77-100.
18. Tabbal SD. Childhood Dystonias. Current Treatment Options in Neurology. 2015;17(3):1-25.
19. Hasnat MJ, Rice JE. Intrathecal Baclofen for Treating Spasticity in Children with Cerebral Palsy. Cochrane
Database Syst Rev. 2015(11):CD004552.
20. Fehlings D, Brown L, Harvey A, Himmelmann K, Lin JP, et al. Pharmacological and Neurosurgical
Interventions for Managing Dystonia in Cerebral Palsy: A Systematic Review. Dev Med Child Neurol.
2018;60(4):356-66.
21. Cloud LJ, Jinnah HA. Treatment Strategies for Dystonia. Expert Opin Pharmacother. 2010;11(1):5-15.
22. Bertucco M, Sanger TD. Current and Emerging Strategies for Treatment of Childhood Dystonia. Journal of
Hand Therapy. 2015;28(2):185-94.
23. Lumsden DE, Kaminska M, Tomlin S, Lin JP. Medication Use in Childhood Dystonia. Eur J Paediatr Neurol.
2016;20(4):625-9.
24. Ramezani S, Amiini N, Khodaei F, Safakheil H, Sarveazad A, et al. A Novel Intervention Technology for
Cerebral Palsy: Brain Stimulation. Iranian Journal of Child Neurology. 2019;13(2):17-28.
25. Aravamuthan BR, Waugh JL, Stone SS. Deep Brain Stimulation for Monogenic Dystonia. Current Opinion in
Pediatrics. 2017;29(6):691-96.
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 61
26. Cook DJ, Mulrow CD, Haynes RB. Systematic Reviews: Synthesis of Best Evidence for Clinical Decisions. Ann
Intern Med. 1997;126(5):376-80.
27. Barry MJ, VanSwearingen JM, Albright AL. Reliability and Responsiveness of the Barry-Albright Dystonia
Scale. Dev Med Child Neurol. 1999;41(6):404-11.
28. Burke RE, Fahn S, Marsden CD, Bressman SB, Moskowitz C, et al. Validity and Reliability of a Rating Scale for
the Primary Torsion Dystonias. Neurology. 1985;35(1):73-7.
29. Frucht SJ, Leurgans SE, Hallett M, Fahn S. The Unified Myoclonus Rating Scale. Adv Neurol. 2002;89:361-76.
30. Law M, Baptiste S, McColl M, Opzoomer A, Polatajko H, et al. The Canadian Occupational Performance
Measure: An Outcome Measure for Occupational Therapy. Can J Occup Ther. 1990;57(2):82-7.
31. Olaya JE, Christian E, Ferman D, Luc Q, Krieger MD, et al. Deep Brain Stimulation in Children and Young
Adults with Secondary Dystonia: The Children's Hospital Los Angeles Experience. Neurosurgical focus.
2013;35(5):E7.
32. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, et al. Amstar 2: A Critical Appraisal Tool for Systematic
Reviews That Include Randomised or Non-Randomised Studies of Healthcare Interventions, or Both. BMJ.
2017;358:j4008.
33. Guo B, Moga C, Harstall C, Schopflocher D. A Principal Component Analysis Is Conducted for a Case Series
Quality Appraisal Checklist. J Clin Epidemiol. 2016;69:199-207 e2.
34. (NHMRC) NHaMRC. Nhmrc Levels of Evidence and Grades for Recommendations for Developers of
Guidelines. Canberra, Australia: NHMRC; 2009. Available from:
https://www.mja.com.au/sites/default/files/NHMRC.levels.of.evidence.2008-09.pdf
35. Merlin T, Weston A, Tooher R. Extending an Evidence Hierarchy to Include Topics Other Than Treatment:
Revising the Australian 'Levels of Evidence'. BMC Med Res Methodol. 2009;9:34.
36. Benato A, Carecchio M, Burlina A, Paoloni F, Sartori S, et al. Long-Term Effect of Subthalamic and Pallidal
Deep Brain Stimulation for Status Dystonicus in Children with Methylmalonic Acidemia and Gnao1
Mutation. Journal of Neural Transmission. 2019
37. Canaz H, Karalok I, Topcular B, Agaoglu M, Yapici Z, et al. Dbs in Pediatric Patients: Institutional Experience.
Child's Nervous System. 2018;34(9):1771-76.
38. Candela S, Vanegas MI, Darling A, Ortigoza-Escobar JD, Alamar M, et al. Frameless Robot-Assisted Pallidal
Deep Brain Stimulation Surgery in Pediatric Patients with Movement Disorders: Precision and Short-Term
Clinical Results. Journal of Neurosurgery: Pediatrics. 2018;22(4):416-25.
39. Koy A, Bockhorn N, Kuhn AA, Schneider GH, Krause P, et al. Adverse Events Associated with Deep Brain
Stimulation in Patients with Childhood-Onset Dystonia. Brain Stimulation. 2019
40. Koy A, Cirak S, Gonzalez V, Becker K, Roujeau T, et al. Deep Brain Stimulation Is Effective in Pediatric
Patients with Gnao1 Associated Severe Hyperkinesia. Journal of the Neurological Sciences. 2018;391:31-39.
41. Lobato-Polo J, Ospina-Delgado D, Orrego-Gonzalez E, Gomez-Castro JF, Orozco JL, et al. Deep Brain
Stimulation Surgery for Status Dystonicus: A Single-Center Experience and Literature Review. World
Neurosurgery. 2018;114:e992-e1001.
42. Tustin K, Elze MC, Lumsden DE, Gimeno H, Kaminska M, et al. Gross Motor Function Outcomes Following
Deep Brain Stimulation for Childhood-Onset Dystonia: A Descriptive Report. European Journal of Paediatric
Neurology. 2019
43. Waak M, Mohammad SS, Coman D, Sinclair K, Copeland L, et al. Gnao1-Related Movement Disorder with
Life-Threatening Exacerbations: Movement Phenomenology and Response to Dbs. J Neurol Neurosurg
Psychiatry. 2018;89(2):221-22.
44. Brimley C, Kershenovich A. Deep Brain Stimulation Lead Migration in a Child Secondary to Osteogenesis at
the Burr Hole Site. Interdisciplinary Neurosurgery: Advanced Techniques and Case Management.
2018;12:27-29.
45. Barbosa B, Carra RB, Duarte KP, Godinho F, de Andrade DC, et al. Bilateral Subthalamic Nucleus Stimulation
in Refractory Status Dystonicus. J Neurol Sci. 2018;388:159-61.
46. Honey CM, Malhotra AK, Tarailo-Graovac M, van Karnebeek CDM, Horvath G, et al. Gnao1 Mutation-
Induced Pediatric Dystonic Storm Rescue with Pallidal Deep Brain Stimulation. Journal of Child Neurology.
2018;33(6):413-16.
47. Jones HF, Morales-Briceno H, Barwick K, Lewis J, Sanchis-Juan A, et al. Myoclonus-Dystonia Caused by
Gnb1 Mutation Responsive to Deep Brain Stimulation. Mov Disord. 2019
48. Oterdoom DLM, van Egmond ME, Ascencao LC, van Dijk JMC, Saryyeva A, et al. Reversal of Status
Dystonicus after Relocation of Pallidal Electrodes in Dyt6 Generalized Dystonia. Tremor and other
hyperkinetic movements (New York, NY). 2018;8:530.
62 SAX INSTITUTE | PAEDIATRIC DEEP BRAIN STIMULATION
49. Skogseid IM, Rosby O, Konglund A, Connelly JP, Nedregaard B, et al. Dystonia-Deafness Syndrome Caused
by Actb P.Arg183trp Heterozygosity Shows Striatal Dopaminergic Dysfunction and Response to Pallidal
Stimulation. J Neurodev Disord. 2018;10(1):17.
50. Robinson KA, Chou R, Berkman ND, Newberry SJ, Fu R, et al. Twelve Recommendations for Integrating
Existing Systematic Reviews into New Reviews: Epc Guidance. J Clin Epidemiol. 2016;70:38-44.
51. Bronte-Stewart H, Taira T, Valldeoriola F, Merello M, Marks WJ, et al. Inclusion and Exclusion Criteria for
Dbs in Dystonia. Movement Disorders. 2011;26(SUPPL.1):S5-S16.
52. Lai JS, Nowinski C, Victorson D, Bode R, Podrabsky T, et al. Quality-of-Life Measures in Children with
Neurological Conditions: Pediatric Neuro-Qol. Neurorehabil Neural Repair. 2012;26(1):36-47.
53. Russel DJ RP, Wright M, Avery LM. Gross Motor Function Measure (Gmfm-66 and Gmfm-88) User's Manual.
2nd Edition. Ontario, Canada: 2013.
54. Comella CL, Leurgans S, Wuu J, Stebbins GT, Chmura T, et al. Rating Scales for Dystonia: A Multicenter
Assessment. Mov Disord. 2003;18(3):303-12.
55. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver Agreement for the
Assessment of Handicap in Stroke Patients. Stroke. 1988;19(5):604-7.
56. Narayanan UG, Fehlings D, Weir S, Knights S, Kiran S, et al. Initial Development and Validation of the
Caregiver Priorities and Child Health Index of Life with Disabilities (Cpchild). Dev Med Child Neurol.
2006;48(10):804-12.
57. Alderson LJ, Alderson P, Tan T. Median Life Span of a Cohort of National Institute for Health and Care
Excellence Clinical Guidelines Was About 60 Months. J Clin Epidemiol. 2014;67(1):52-5.
58. Martinez Garcia L, Sanabria AJ, Garcia Alvarez E, Trujillo-Martin MM, Etxeandia-Ikobaltzeta I, et al. The
Validity of Recommendations from Clinical Guidelines: A Survival Analysis. CMAJ. 2014;186(16):1211-9.
59. (WHO) WHO. International Classification of Functioning, Disability and Health (Icf). Geneva: WHO; 2001.
60. Akano E OF, Lavenstein B, Ehrlich D. Indications, Outcomes and Cost of Pediatric Deep Brain Stimulation
Surgeries in the United States: An Analysis of the Kids' Inpatient Sample (P4.8-021). Neurology. 2019;92(15
Supplement)
61. Yianni J, Green AL, McIntosh E, Bittar RG, Joint C, et al. The Costs and Benefits of Deep Brain Stimulation
Surgery for Patients with Dystonia: An Initial Exploration. Neuromodulation. 2005;8(3):155-61.
62. Owen T, Adegboye D, Gimeno H, Selway R, Lin JP. Stable Cognitive Functioning with Improved Perceptual
Reasoning in Children with Dyskinetic Cerebral Palsy and Other Secondary Dystonias after Deep Brain
Stimulation. European Journal of Paediatric Neurology. 2017;21(1):193-201.
63. Austin A, Lin JP, Selway R, Ashkan K, Owen T. What Parents Think and Feel About Deep Brain Stimulation in
Paediatric Secondary Dystonia Including Cerebral Palsy: A Qualitative Study of Parental Decision-Making.
European Journal of Paediatric Neurology. 2017;21(1):185-92.
64. Marks W, Bailey L, Sanger TD. Pedidbs: The Pediatric International Deep Brain Stimulation Registry Project.
European Journal of Paediatric Neurology. 2017;21(1):218-22.
65. Gimeno H, Tustin K, Lumsden D, Ashkan K, Selway R, et al. Evaluation of Functional Goal Outcomes Using
the Canadian Occupational Performance Measure (Copm) Following Deep Brain Stimulation (Dbs) in
Childhood Dystonia. European Journal of Paediatric Neurology. 2014;18(3):308-16.
66. Lumsden DE, Gimeno H, Tustin K, Kaminska M, Lin JP. Interventional Studies in Childhood Dystonia Do Not
Address the Concerns of Children and Their Carers. Eur J Paediatr Neurol. 2015;19(3):327-36.
67. Penner M, Xie WY, Binepal N, Switzer L, Fehlings D. Characteristics of Pain in Children and Youth with
Cerebral Palsy. Pediatrics. 2013;132(2):e407-13.
68. Gimeno H, Lin JP. The International Classification of Functioning (Icf) to Evaluate Deep Brain Stimulation
Neuromodulation in Childhood Dystonia-Hyperkinesia Informs Future Clinical & Research Priorities in a
Multidisciplinary Model of Care. European Journal of Paediatric Neurology. 2017;21(1):147-67.
69. Romito LM, Zorzi G, Marras CE, Franzini A, Nardocci N, et al. Pallidal Stimulation for Acquired Dystonia Due
to Cerebral Palsy: Beyond 5 Years. European Journal of Neurology. 2015;22(3):426-e32.
70. Aydin S, Abuzayed B, Uysal S, Unver O, Uzan M, et al. Pallidal Deep Brain Stimulation in a 5-Year-Old Child
with Dystonic Storm: Case Report. Turk Neurosurg. 2013;23(1):125-8.
71. Jin ST, Lee MK, Ghang JY, Jeon SM. Deep Brain Stimulation of the Globus Pallidus in a 7-Year-Old Girl with
Dyt1 Generalized Dystonia. Journal of Korean Neurosurgical Society. 2012;52(3):261-63.
72. Miri S, Ghoreyshi E, Shahidi GA, Parvaresh M, Rohani M, et al. Deep Brain Stimulation of Globus Pallidus
Internus for Dyt1 Positive Primary Generalized Dystonia. Med J Islam Repub Iran. 2014;28:18.
73. Bhanpuri NH, Bertucco M, Ferman D, Young SJ, Liker MA, et al. Deep Brain Stimulation Evoked Potentials
May Relate to Clinical Benefit in Childhood Dystonia. Brain Stimul. 2014;7(5):718-26.
PAEDIATRIC DEEP BRAIN STIMULATION | SAX INSTITUTE 63
74. Chakraborti S, Hasegawa H, Lumsden DE, Ali W, Kaminska M, et al. Bilateral Subthalamic Nucleus Deep
Brain Stimulation for Refractory Total Body Dystonia Secondary to Metabolic Autopallidotomy in a 4-Year-
Old Boy with Infantile Methylmalonic Acidemia. Journal of Neurosurgery: Pediatrics. 2013;12(4):374-79.
75. Dulski J, Schinwelski M, Mandat T, Pienczk-Reclawowicz K, Slawek J. Long-Term Follow-up with Video of a
Patient with Deafness-Dystonia Syndrome Treated with Dbs-Gpi. Stereotactic and Functional Neurosurgery.
2016;94(2):123-25.
76. Rocha H, Linhares P, Chamadoira C, Rosas MJ, Vaz R. Early Deep Brain Stimulation in Patients with
Myoclonus-Dystonia Syndrome. J Clin Neurosci. 2016;27:17-21.
77. Tsering D, Tochen L, Lavenstein B, Reddy SK, Granader Y, et al. Considerations in Deep Brain Stimulation
(Dbs) for Pediatric Secondary Dystonia. Child's Nervous System. 2017;33(4):631-37.
78. Ben-Haim S, Flatow V, Cheung T, Cho C, Tagliati M, et al. Deep Brain Stimulation for Status Dystonicus: A
Case Series and Review of the Literature. Stereotactic and Functional Neurosurgery. 2016;94(4):207-15.
79. Kaminska M, Perides S, Lumsden DE, Nakou V, Selway R, et al. Complications of Deep Brain Stimulation
(Dbs) for Dystonia in Children - the Challenges and 10 Year Experience in a Large Paediatric Cohort.
European Journal of Paediatric Neurology. 2017;21(1):168-75.
80. Petrossian MT, Paul LR, Multhaupt-Buell TJ, Eckhardt C, Hayes MT, et al. Pallidal Deep Brain Stimulation for
Dystonia: A Case Series. J Neurosurg Pediatr. 2013;12(6):582-7.
81. Marks W, Bailey L, Reed M, Pomykal A, Mercer M, et al. Pallidal Stimulation in Children: Comparison
between Cerebral Palsy and Dyt1 Dystonia. J Child Neurol. 2013;28(7):840-8.
82. Air EL, Ostrem JL, Sanger TD, Starr PA. Deep Brain Stimulation in Children: Experience and Technical Pearls.
J Neurosurg Pediatr. 2011;8(6):566-74.
83. Walcott BP, Nahed BV, Kahle KT, Duhaime AC, Sharma N, et al. Deep Brain Stimulation for Medically
Refractory Life-Threatening Status Dystonicus in Children: Report of 3 Cases. Journal of Neurosurgery:
Pediatrics. 2012;9(1):99-102.
84. Mikati MA, Yehya A, Darwish H, Karam P, Comair Y. Deep Brain Stimulation as a Mode of Treatment of Early
Onset Pantothenate Kinase-Associated Neurodegeneration. European Journal of Paediatric Neurology.
2009;13(1):61-64.
85. Keen JR, Przekop A, Olaya JE, Zouros A, Hsu FP. Deep Brain Stimulation for the Treatment of Childhood
Dystonic Cerebral Palsy. J Neurosurg Pediatr. 2014;14(6):585-93.
86. Lin JP, Kaminska M, Perides S, Gimeno H, Baker L, et al. Bilateral Globus Pallidus Internus Deep Brain
Stimulation for Dyskinetic Cerebral Palsy Supports Success of Cochlear Implantation in a 5-Year Old Ex-24
Week Preterm Twin with Absent Cerebellar Hemispheres. Eur J Paediatr Neurol. 2017;21(1):202-13.
87. Markun LC, Starr PA, Air EL, Marks WJ, Volz MM, et al. Shorter Disease Duration Correlates with Improved
Long-Term Deep Brain Stimulation Outcomes in Young-Onset Dyt1 Dystonia. Neurosurgery.
2012;71(2):325-30.
88. Starr PA, Markun LC, Larson PS, Volz MM, Martin AJ, et al. Interventional Mri-Guided Deep Brain
Stimulation in Pediatric Dystonia: First Experience with the Clearpoint System. Journal of Neurosurgery:
Pediatrics. 2014;14(4):400-08.
89. Liu Z, Liu Y, Yang Y, Wang L, Dou W, et al. Subthalamic Nuclei Stimulation in Patients with Pantothenate
Kinase-Associated Neurodegeneration (Pkan). Neuromodulation. 2017;20(5):484-91.
90. Miyagi Y, Koike Y. Tolerance of Early Pallidal Stimulation in Pediatric Generalized Dystonia. J Neurosurg
Pediatr. 2013;12(5):476-82.
91. Hyam JA, de Pennington N, Joint C, Green AL, Owen SL, et al. Maintained Deep Brain Stimulation for Severe
Dystonia Despite Infection by Using Externalized Electrodes and an Extracorporeal Pulse Generator. J
Neurosurg. 2010;113(3):630-3.
92. Vidailhet M, Yelnik J, Lagrange C, Fraix V, Grabli D, et al. Bilateral Pallidal Deep Brain Stimulation for the
Treatment of Patients with Dystonia-Choreoathetosis Cerebral Palsy: A Prospective Pilot Study. Lancet
Neurol. 2009;8(8):709-17.